Publications by authors named "Fengjing Guo"

61 Publications

Growth differentiation factor 5 in cartilage and osteoarthritis: A possible therapeutic candidate.

Cell Prolif 2021 Mar 1;54(3):e12998. Epub 2021 Feb 1.

Department of Orthopedics, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.

Growth differentiation factor 5 (GDF-5) is essential for cartilage development and homeostasis. The expression and function of GDF-5 are highly associated with the pathogenesis of osteoarthritis (OA). OA, characterized by progressive degeneration of joint, particularly in cartilage, causes severe social burden. However, there is no effective approach to reverse the progression of this disease. Over the past decades, extensive studies have demonstrated the protective effects of GDF-5 against cartilage degeneration and defects. Here, we summarize the current literature describing the role of GDF-5 in development of cartilage and joints, and the association between the GDF-5 gene polymorphisms and OA susceptibility. We also shed light on the protective effects of GDF-5 against OA in terms of direct GDF-5 supplementation and modulation of the GDF-5-related signalling. Finally, we discuss the current limitations in the application of GDF-5 for the clinical treatment of OA. This review provides a comprehensive insight into the role of GDF-5 in cartilage and emphasizes GDF-5 as a potential therapeutic candidate in OA.
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http://dx.doi.org/10.1111/cpr.12998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941218PMC
March 2021

Chondrocyte ferroptosis contribute to the progression of osteoarthritis.

J Orthop Translat 2021 Mar 17;27:33-43. Epub 2020 Dec 17.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, PR China.

Background: Osteoarthritis (OA) is a complex process comprised of mechanical load, inflammation, and metabolic factors. It is still unknown that if chondrocytes undergo ferroptosis during OA and if ferroptosis contribute to the progression of OA.

Materials And Methods: In our study, we use Interleukin-1 Beta (IL-1β) to simulate inflammation and ferric ammonium citrate (FAC) to simulate the iron overload . Also, we used the surgery-induced destabilized medial meniscus (DMM) mouse model to induce OA . We verify ferroptosis by its definition that defined by the Nomenclature Committee on Cell Death with both and model.

Results: We observed that both IL-1β and FAC induced reactive oxygen species (ROS), and lipid ROS accumulation and ferroptosis related protein expression changes in chondrocytes. Ferrostatin-1, a ferroptosis specific inhibitor, attenuated the cytotoxicity, ROS and lipid-ROS accumulation and ferroptosis related protein expression changes induced by IL-1β and FAC and facilitated the activation of Nrf2 antioxidant system. Moreover, erastin, the most classic inducer of ferroptosis, promoted matrix metalloproteinase 13 (MMP13) expression while inhibited type II collagen (collagen II) expression in chondrocytes. At last, we proved that intraarticular injection of ferrostatin-1 rescued the collagen II expression and attenuated the cartilage degradation and OA progression in mice OA model.

Conclusions: In summary, our study firstly proved that chondrocytes underwent ferroptosis under inflammation and iron overload condition. Induction of ferroptosis caused increased MMP13 expression and decreased collagen II expression in chondrocytes. Furthermore, inhibition of ferroptosis, by intraarticular injection of ferrostatin-1, in our case, seems to be a novel and promising option for the prevention of OA.

The Translational Potential Of This Article: The translation potential of this article is that we first indicated that chondrocyte ferroptosis contribute to the progression of osteoarthritis which provides a novel strategy in the prevention of OA.
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http://dx.doi.org/10.1016/j.jot.2020.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750492PMC
March 2021

Hyperoside ameliorates the progression of osteoarthritis: An in vitro and in vivo study.

Phytomedicine 2021 Jan 14;80:153387. Epub 2020 Oct 14.

Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address:

Background: Osteoarthritis (OA) is a common degenerative joint disease. The pathogenesis of OA is closely related to inflammatory responses and apoptosis of chondrocytes. Hyperoside (Hyp), a natural flavonoid compound, exerts multiple bioactivities in various diseases.

Purpose: Our study aims to investigate the anti-arthritic effects of Hyp and delineate the potential mechanism at the cellular level.

Methods: Murine chondrocytes were stimulated with interleukin-1β (IL-1β) with or without Hyp treatment. CCK-8 assay was used to evaluate the cytotoxic effect of Hyp. DCFH-DA was used to detect intracellular ROS. Annexin V-FITC/PI method was applied to examine apoptosis of chondrocytes. The anti-arthritic effects of Hyp and related mechanisms were investigated by examining and analyzing relative markers through quantitative PCR, western blot analysis and immunofluorescent staining. C57BL/6 mice were performed the destabilized medial meniscus (DMM) surgery to establish OA model and then injected intraperitoneally with Hyp (20 mg/kg)) for 4 or 8 weeks. Finally, mice were sacrificed and knee joints were collected for histological observation and analysis.

Results: Hyp inhibited IL-1β-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Additionally, Hyp attenuated IL-1β-induced destruction of the extracellular matrix (ECM) by downregulating the expression of MMPs and ADAMTS5, and meanwhile upregulating the expression of collagen II, aggrecan, and SOX9. Also, Hyp pretreatment reduced IL-1β-induced overproduction of ROS and apoptosis of chondrocytes. Mechanistically, Hypexerted anti-inflammatory effects by partly suppressing the PI3K/AKT/NF-κB and the MAPK signaling pathways, enhancing the Nrf2/HO-1 to limit the activation of NF-κB. Moreover, Hyp played an anti-apoptotic effect via the Nrf2/ROS/BAX/Bcl-xlaxis. In vivo, cartilage degradation was attenuated with a lower OARSI score in Hyp-treated group compared to the DMM group.

Conclusion: Our study demonstrated that anti-arthritic effects of Hyp in vitro and in vivo, indicating Hyp might serve as a potential agent for the treatment of OA.
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http://dx.doi.org/10.1016/j.phymed.2020.153387DOI Listing
January 2021

PERK controls bone homeostasis through the regulation of osteoclast differentiation and function.

Cell Death Dis 2020 10 13;11(10):847. Epub 2020 Oct 13.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, 430030, Wuhan, China.

Osteoclasts are multinucleated giant cells with the ability to degrade bone tissue, and are closely related to abnormal bone metabolic diseases. Endoplasmic reticulum (ER) is an organelle responsible for protein modification, quality control, and transportation. The accumulation of unfolded or misfolded proteins in ER cavity induces ER stress. Double-stranded RNA-dependent protein kinase-like ER kinase (PERK) is an ER stress-sensing protein, which is ubiquitous in eukaryotic cells. Systemic PERK knockout mice show severe bone loss, suggesting that PERK is of great significance for maintaining the normal growth and development of bone tissue, but the role of PERK in osteoclastogenesis is still unclear. In this study, we found that PERK was significantly activated during RANKL-induced osteoclast differentiation; knockdown of PERK by siRNA and inhibition of PERK by GSK2606414, respectively, had significant negative regulatory effects on the formation and bone resorption of osteoclasts. PERK inhibitor GSK2606414 down-regulated the mRNA levels and protein expression of osteoclast differentiation marker genes, and inhibited RANKL-induced activation of Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways. Treatment with PERK inhibitor GSK2606414 in ovariectomized mouse model significantly suppressed bone loss and osteoclast formation. Thapsigargin activated ER stress to enhance autophagy, while GSK2606414 had a significant inhibitory effect on autophagy flux and autophagosome formation. Antioxidant N-acetylcysteine (NAC) could inhibit the expression of PERK phosphorylation, osteoclast-related proteins and autophagy-related proteins, but the use of PERK activator CCT020312 can reverse inhibition effect of NAC. Our findings demonstrate a key role for PERK in osteoclast differentiation and suggest its therapeutic potential.
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http://dx.doi.org/10.1038/s41419-020-03046-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554039PMC
October 2020

Mitophagy in degenerative joint diseases.

Autophagy 2020 Sep 24:1-11. Epub 2020 Sep 24.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Mitochondrial dysfunction is involved in aging and multiple degenerative diseases, including intervertebral disc degeneration (IVDD) and osteoarthritis (OA). Thus, the maintenance of mitochondria homeostasis and function is important. Mitophagy, a process that selectively clears damaged or dysfunctional mitochondria through autophagic machinery, functions to maintain mitochondrial quality control and homeostasis. IVDD and OA are similar joint diseases involving the degradation of cartilaginous tissues that are mainly caused by oxidative stress, cell apoptosis and extracellular matrix (ECM) degradation. Over the past decade, accumulating evidence indicates the essential role of mitophagy in the pathogenesis of IVDD and OA. Importantly, strategies by the regulation of mitophagy exert beneficial effects in the pre-clinical experiments. Given the importance and novelty of mitophagy, we provide an overview of mitophagy pathways and discuss the roles of mitophagy in IVDD and OA. We also highlight the potential of targeting mitophagy for the treatment of degenerative joint diseases. AD: Alzheimer disease; AF: annulus fibrosus; ADORA2A/A2AR: adenosine A2a receptor; AMBRA1: autophagy and beclin 1 regulator 1; BMSCs: bone marrow mesenchymal stem cells; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; CDH6: cadherin 6; CEP: cartilaginous endplates; circRNA: circular RNA; DNM1L/DRP1: dynamin 1-like; ECM: extracellular matrix; HIF1A: hypoxia inducible factor 1: alpha subunit; IL1B: interleukin 1 beta; IMM: inner mitochondrial membranes; IVDD: intervertebral disc degeneration; MAPK8/JNK: mitogen-activated protein kinase 8; MFN1: mitofusin 1; MFN2: mitofusin 2; MIA: monosodium iodoacetate; RHOT/MIRO: ras homolog family member T; MMP: mitochondrial transmembrane potential; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; NFE2L2: nuclear factor: erythroid 2 like 2; NP: nucleus pulposus; OA: osteoarthritis; OPA1: OPA1: mitochondrial dynamin like GTPase; OPTN: optineurin; PRKN: parkin RBR E3 ubiquitin protein ligase; PD: Parkinson disease; PGAM5: PGAM family member 5; PPARGC1A/PGC-1A: peroxisome proliferator activated receptor: gamma: coactivator 1 alpha; PHF23: PHD finger protein 23; PINK1: PTEN induced putative kinase 1; ROS: reactive oxygen species; SfMSCs: synovial fluid MSCs; SIRT1: sirtuin 1; SIRT2: sirtuin 2; SIRT3: sirtuin 3; SQSTM1/p62: sequestosome 1; TNF: tumor necrosis factor; Ub: ubiquitin; UBL: ubiquitin-like; VDAC: voltage-dependent anion channel.
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http://dx.doi.org/10.1080/15548627.2020.1822097DOI Listing
September 2020

Correction: Inhibition of microRNA-384-5p alleviates osteoarthritis through its effects on inhibiting apoptosis of cartilage cells via the NF-κB signaling pathway by targeting SOX9.

Cancer Gene Ther 2020 Nov;27(10-11):836-837

Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, P.R. China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41417-020-0202-yDOI Listing
November 2020

PTEN inhibitor VO-OHpic attenuates GC-associated endothelial progenitor cell dysfunction and osteonecrosis of the femoral head via activating Nrf2 signaling and inhibiting mitochondrial apoptosis pathway.

Stem Cell Res Ther 2020 03 30;11(1):140. Epub 2020 Mar 30.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.

Background: Glucocorticoid (GC)-associated osteonecrosis of the femoral head (ONFH) is the most common in non-traumatic ONFH. Despite a strong relationship between GC and ONFH, the detailed mechanisms have remained elusive. Recent studies have shown that GC could directly injure the blood vessels and reduce blood supply in the femoral head. Endothelial progenitor cells (EPCs), which were inhibited quantitatively and functionally during ONFH, play an important role in maintaining the normal structure and function of vascular endothelium. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene that promotes cell apoptosis, and its expression was found to be elevated in GC-associated ONFH patients. However, whether direct inhibition of PTEN attenuates GC-associated apoptosis and dysfunction of the EPCs remains largely unknown.

Methods: We investigated the effect of, VO-OHpic, a potent inhibitor of PTEN, in attenuating GC-associated apoptosis and dysfunction of EPCs and the molecular mechanism. SD rats were used to study the effect of VO-OHpic on angiogenesis and osteonecrosis in vivo.

Results: The results revealed that methylprednisolone (MPS) obviously inhibit angiogenesis of EPCs by inducing apoptosis, destroying the normal mitochondrial structure, and disrupting function of mitochondria. VO-OHpic treatment is able to reverse the harmful effects by inhibiting the mitochondrial apoptosis pathway and activating the NF-E2-related factor 2 (Nrf2) signaling. Si-Nrf2 transfection significantly reduced the protective effects of VO-OHpic on EPCs. Our in vivo studies also showed that intraperitoneal injection of VO-OHpic obviously attenuates the osteonecrosis of the femoral head induced by MPS and potently increases the blood supply in the femoral head.

Conclusion: Taken together, the data suggests that inhibition of PTEN with VO-OHpic attenuates apoptosis and promotes angiogenesis of EPCs in vitro via activating Nrf2 signaling pathway and inhibiting the mitochondrial apoptosis pathway. Moreover, VO-OHpic also mitigates GC-associated ONFH and potentiates angiogenesis in the femoral head.
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http://dx.doi.org/10.1186/s13287-020-01658-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106818PMC
March 2020

PKM2 suppresses osteogenesis and facilitates adipogenesis by regulating β-catenin signaling and mitochondrial fusion and fission.

Aging (Albany NY) 2020 02 25;12(4):3976-3992. Epub 2020 Feb 25.

Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Bone marrow mesenchymal stem cells (BMSCs) differentiation dysfunction is a common pathological phenotype of several prevalent metabolic and genetic bone diseases. Pyruvate kinase muscle isoenzyme 2 (PKM2) regulates the last step of glycolysis, and its role in BMSCs differentiation is still unknown. In this study, the influence of PKM2 on osteogenesis and adipogenesis was assessed in vitro and in vivo. We found that DASA-58 (the activator of PKM2) reduced the enzymatic activity of ALP, and inhibited the levels of osteogenic marker genes, especially RUNX2, which is a crucial transcription factor for osteogenesis. Besides, we provided evidence that C3k, an inhibitor of PKM2, caused increase in mitochondrial membrane potential and maintained low levels of ROS, and promoted mitochondrial fusion. Furthermore, after treatment with DASA-58, the level of active β-catenin gradually decreased, which also inhibited the transport of active β-catenin into the nucleus, but C3k obviously promoted its nuclear translocation. As for adipogenesis, PKM2 activation increased the expression of adipogenic related genes and decreased active-β-catenin expression, whereas treatment of C3k had the opposite effect. In addition, C3k significantly attenuated ovariectomy-induced trabecular bone loss in vivo. Our findings helped uncover the molecular mechanisms underlying PKM2 regulation of BMSCs differentiation.
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http://dx.doi.org/10.18632/aging.102866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066892PMC
February 2020

NR1D1 modulates synovial inflammation and bone destruction in rheumatoid arthritis.

Cell Death Dis 2020 02 18;11(2):129. Epub 2020 Feb 18.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia, pannus formation, and cartilage and bone destruction. Nuclear receptor subfamily 1 group D member 1 (NR1D1) functions as a transcriptional repressor and plays a vital role in inflammatory reactions. However, whether NR1D1 is involved in synovial inflammation and joint destruction during the pathogenesis of RA is unknown. In this study, we found that NR1D1 expression was increased in synovial tissues from patients with RA and decreased in RA Fibroblast-like synoviocytes (FLSs) stimulated with IL-1β in vitro. We showed that NR1D1 activation decreased the expression of proinflammatory cytokines and matrix metalloproteinases (MMPs), while NR1D1 silencing exerted the opposite effect. Furthermore, NR1D1 activation reduced reactive oxygen species (ROS) generation and increased the production of nuclear transcription factor E2-related factor 2 (Nrf2)-associated enzymes. Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways were blocked by the NR1D1 agonist SR9009 but activated by NR1D1 silencing. NR1D1 activation also inhibited M1 macrophage polarization and suppressed osteoclastogenesis and osteoclast-related genes expression. Treatment with NR1D1 agonist SR9009 in collagen-induced arthritis (CIA) mouse significantly suppressed the hyperplasia of synovial, infiltration of inflammatory cell and destruction of cartilage and bone. Our findings demonstrate an important role for NR1D1 in RA and suggest its therapeutic potential.
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http://dx.doi.org/10.1038/s41419-020-2314-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028921PMC
February 2020

Astaxanthin protects against osteoarthritis via Nrf2: a guardian of cartilage homeostasis.

Aging (Albany NY) 2019 11 26;11(22):10513-10531. Epub 2019 Nov 26.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

Scope: Osteoarthritis (OA) is a progressive disease characterized by cartilage degradation. Astaxanthin (Ast), a natural compound with remarkable antioxidant activity and multiple medical applications due to its activation of Nrf2 signaling, has been studied for application to various degenerative diseases. Currently, however, little is known about its efficacy in treating OA. This study reports the effects of Ast on cartilage homeostasis in OA progression.

Methods: IL-1β, TNF-α, and tert-butyl hydroperoxide (TBHP) were used to impair cartilage homeostasis. Modulating effects of Ast on the Nrf2 signaling pathway, and damage-associated events including extracellular matrix (ECM) degradation, inflammation, oxidative stress, chondrocyte apoptosis, and cartilage degradation were examined.

Results: Ast attenuated ECM degradation of OA chondrocytes through the Nrf2 signaling, and ameliorated the IL-1β-induced inflammatory response and ECM degradation via blockade of MAPK signaling. Additionally, Ast alleviated TNF-α-induced ECM degradation and chondrocyte apoptosis by inhibiting the NF-κB signaling, suppressed TBHP-induced oxidative stress, and subsequently reduced chondrocyte apoptosis. results were finally corroborated by demonstrating that Ast attenuates the severity of cartilage destruction in a mouse model of OA.

Conclusions: Ast could protect against osteoarthritis via the Nrf2 signaling, suggesting Ast might be a potential therapeutic supplement for OA treatment.
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http://dx.doi.org/10.18632/aging.102474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914430PMC
November 2019

A new PEGDA/CNF aerogel-wet hydrogel scaffold fabricated by a two-step method.

Soft Matter 2019 Oct 4;15(40):8092-8101. Epub 2019 Oct 4.

School of Mechanical and Automotive Engineering, South China University of Technology, 381 Wushan Road, Guangzhou, Guangdong, CN 510640, China.

The scaffold is one of the most important components in tissue engineering. There are a lot of natural or synthetic materials applied for the fabrication of scaffolds. Among them, cellulose nanofibril (CNF) is an important natural polymer with characteristics of superior biocompatibility, notable nanostructure effect and excellent hydrophilia, which make it qualified for serving as a raw material of scaffolds. In this paper, polyethylene glycol diacrylate (PEGDA) was mixed with CNF at different content ratios, which were 0%, 0.35%, 0.7%, 1.05% and 1.4% (m/v). Furthermore, the visible light photoinitiator (eosin Y + TEA + NVP) was first added to this mixture solution to form a new kind of bio-resin. A two-step method including stereolithography and freeze-drying is put forward to fabricate a new aerogel-wet hydrogel scaffold. Scaffolds were fabricated by using a self-built stereolithography platform and the mechanical properties, printability and biocompatibility of the hydrogel scaffolds were investigated thoroughly. The original hydrogel scaffold was fabricated through stereolithography, where CNFs were applied to regulate the mechanical properties of the hydrogel and the printability of the bio-resin. After the freeze-drying process, the original hydrogel was transformed into the aerogel-wet hydrogel whose compressive modulus is reduced by 20%. Furthermore, the surface structure of the hydrogel scaffold is modified to provide a better environment for adhesion and growth of BMSc.
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http://dx.doi.org/10.1039/c9sm00899cDOI Listing
October 2019

Integrative analyses of key genes and regulatory elements in fluoride-affected osteosarcoma.

J Cell Biochem 2019 09 29;120(9):15397-15409. Epub 2019 Apr 29.

Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Osteosarcoma is one of the most malignant tumors in adolescents with severe outcomes while fluoride is one of the most abundant elements in the environment. Epidemiological evidence has elucidated the relationship between fluoride and osteosarcoma, but the molecular mechanisms are extremely complicated. Microarray profiles were downloaded from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) in the progression of fluoride-affected osteosarcoma. The functional enrichment analysis was performed, a protein-protein interaction network, a microRNA-messenger RNA (mRNA) and a transcription factors-mRNA regulatory network were constructed and performed using Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape. A total of 171 DEGs were identified. The functions and pathways of the DEGs were enriched in nucleolus, protein ubiquitination, protein binding, RNA transport, and the spliceosome. Eighteen hub genes were identified and functional analysis revealed that these genes are mainly enriched in protein binding, nucleoplasm, and ribosomal RNA processing. Survival analysis showed that the hub genes may be involved in the invasion or recurrence of osteosarcoma. In conclusion, the DEGs and hub genes with their regulatory elements identified in this study will help us understand the molecular mechanisms underlying fluoride-affected osteosarcoma and provide candidate targets for future research.
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http://dx.doi.org/10.1002/jcb.28807DOI Listing
September 2019

Icariin Protects Bone Marrow Mesenchymal Stem Cells Against Iron Overload Induced Dysfunction Through Mitochondrial Fusion and Fission, PI3K/AKT/mTOR and MAPK Pathways.

Front Pharmacol 2019 28;10:163. Epub 2019 Feb 28.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Iron overload has been reported to contribute to bone marrow mesenchymal stem cells (BMSCs) damage, but the precise mechanism still remains elusive. Icariin, a major bioactive monomer belonging to flavonoid glucosides isolated from Herba Epimedii, has been shown to protect cells from oxidative stress induced apoptosis. The aim of this study was to investigate whether icariin protected against iron overload induced dysfunction of BMSCs and its underlying mechanism. In this study, we found that iron overload induced by 100 μM ferric ammonium citrate (FAC) caused apoptosis of BMSCs, promoted cleaved caspase-3 and BAX protein expressions while inhibited Bcl-2 protein expression, which effects were significantly attenuated by icariin treatment. In addition, iron overload induced significant depolarization of mitochondrial membrane potential (MMP), reactive oxygen species (ROS) generation and inhibition of mitochondrial fusion/fission, which effects were also attenuated by icariin treatment. Meanwhile, we found that iron overload induced by 100 μM FAC significantly inhibited mitochondrial fission protein FIS1 and fusion protein MFN2 expressions, inhibited DRP1 and Cytochrome C protein translocation from the cytoplasm to mitochondria. Icariin at concentration of 1 μM was able to promote mitochondrial fission protein FIS1 and fusion protein MFN2 expressions, and increase DRP1 and cytochrome C protein translocation from the cytoplasm to mitochondria. Further, osteogenic differentiation and proliferation of BMSCs was significantly inhibited by iron overload, but icariin treatment rescued both osteogenic differentiation and proliferation of BMSCs. Further studies showed that icariin attenuated iron overload induced inactivation of the PI3K/AKT/mTOR pathway and activation of the ERK1/2 and JNK pathways. In summary, our study indicated that icariin was able to protect against iron overload induced dysfunction of BMSCs. These effects were potentially related to the modulation of mitochondrial fusion and fission, activation of the PI3K/AKT/mTOR pathway and inhibition of ERK1/2 and JNK pathways.
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http://dx.doi.org/10.3389/fphar.2019.00163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403125PMC
February 2019

Primary cilia and autophagy interaction is involved in mechanical stress mediated cartilage development via ERK/mTOR axis.

Life Sci 2019 Feb 3;218:308-313. Epub 2019 Jan 3.

Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address:

Aims: Biomechanical reactivity is a special property of chondrocytes and mechanical stress can affect the development of cartilage. Primary cilia have been proved a cellular sensory which can detect physical and chemical stimuli extracellular and initiate multiple signaling transduction. Autophagy is an important environmental adaptive mechanism for cells maintenance of homeostasis. The aims of this study were to detect whether there is an interaction between primary cilia and autophagy in the regulation of mechanical stress-mediated cartilage development and to explore the underlying mechanism.

Main Methods: In this study, chondrocytes were treated with cyclic tensile strain (CTS) by the four-point bending system. Chondrocytes viability, proliferation and differentiation capacities were analyzed by western blot and live/dead assays after CTS of different intensities. Meanwhile, primary cilia incidence and length changes, and autophagy expression were detected by immunofluorescence staining. The primary cilia and autophagy interaction regulation and the underlying mechanism were detected by immunofluorescence double staining and western blot.

Key Findings: Mechanical stress could affect chondrocytes proliferation, phenotype and viability in an intensity dependent manner. The incidence and length of primary cilia as well as autophagy expression could be regulated by CTS. The integrity of primary cilia structure is vital for mechanical stress regulated ERK/mTOR signaling transduction and autophagy expression in chondrocyte.

Significance: These findings indicate that mechanical stress could affect the interaction between primary cilia and autophagy and help to reveal the underlying mechanism of stress regulated cartilage development.
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http://dx.doi.org/10.1016/j.lfs.2019.01.001DOI Listing
February 2019

Hesperetin suppresses RANKL-induced osteoclastogenesis and ameliorates lipopolysaccharide-induced bone loss.

J Cell Physiol 2019 07 11;234(7):11009-11022. Epub 2018 Dec 11.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Destructive bone diseases caused by osteolysis are increasing in incidence. They are characterized by an excessive imbalance of osteoclast formation and activation. During osteolysis, the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways are triggered by receptor activator of NF-κB ligand (RANKL), inflammatory factors, and oxidative stress. Previous studies have indicated that the common flavanone glycoside compound hesperetin exhibits anti-inflammatory and antioxidant activity by inhibition of NF-κB and MAPK signaling pathways. However, the direct relationship between hesperetin and osteolysis remain unclear. In the present study, we investigated the effects of hesperetin on lipopolysaccharide (LPS)-induced osteoporosis and elucidated the related mechanisms. Hesperetin effectively suppressed RANKL-induced osteoclastogenesis, osteoclastic bone resorption, and F-actin ring formation in a dose-dependent manner. It also significantly suppressed the expression of osteoclast-specific markers including tartrate-resistant acid phosphatase, matrix metalloproteinase-9, cathepsin K, c-Fos, and nuclear factor of activated T-cells cytoplasmic 1. Furthermore, it inhibited osteoclastogenesis by inhibiting activation of NF-κB and MAPK signaling, scavenging reactive oxygen species, and activating the nuclear factor E2 p45-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway. Consistent with in vitro results, hesperetin effectively ameliorated LPS-induced bone loss, reduced osteoclast numbers, and decreased the RANKL/OPG ratio in vivo. As such, our results suggest that hesperetin may be a great candidate for developing a novel drug for destructive bone diseases such as periodontal disease, tumor bone metastasis, rheumatoid arthritis, and osteoporosis.
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http://dx.doi.org/10.1002/jcp.27924DOI Listing
July 2019

Icariin protects against iron overload-induced bone loss via suppressing oxidative stress.

J Cell Physiol 2019 07 1;234(7):10123-10137. Epub 2018 Nov 1.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Iron overload is common in patients with diseases such as hemoglobinopathies, hereditary hemochromatosis or elderly men and postmenopausal women. This disorder is frequently associated with bone loss and recently has been considered as an independent risk factor for osteoporosis. By excess reactive oxygen species (ROS) production through Fenton reaction, iron could induce osteoblast apoptosis, inhibit osteoblast osteogenic differentiation. Moreover, Iron could also promote osteoclasts differentiation and bone absorption. The goal of the study is to investigate whether icariin could reverse iron overload-induced bone loss in vitro and in vivo. Icariin is the major active ingredient of Herba Epimedii and has antioxidant, antiosteoporosis functions. In the current study, we demonstrated that oral administration of icariin significantly prevented bone loss in iron overloaded mice. Icariin could protect against iron overload-induced mitochondrial membrane potential dysfunction and ROS production, promote osteoblast survival and reverse the reduction of Runx2, alkaline phosphatase, and osteopontin expression induced by iron overload. Icariin also inhibited osteoclasts differentiation and function. Moreover, we also found that icariin remarkably reduced iron accumulation in bone marrow, suggesting that icariin has the ability to regulate systemic iron metabolism in vivo. These results indicated that icariin could be a potential natural resource for developing medicines to prevent or treat iron overload-induced osteoporosis.
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http://dx.doi.org/10.1002/jcp.27678DOI Listing
July 2019

Hypoxia promotes maintenance of the chondrogenic phenotype in rat growth plate chondrocytes through the HIF-1α/YAP signaling pathway.

Int J Mol Med 2018 Dec 9;42(6):3181-3192. Epub 2018 Oct 9.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.

The Hippo‑yes‑associated protein (YAP) signaling pathway was previously identified to serve an important role in controlling chondrocyte differentiation and post‑natal growth. Growth plate cartilage tissue is avascular, and hypoxia‑inducible factor (HIF)‑1α is essential for chondrocytes to maintain their chondrogenic phenotype in a hypoxic environment. In the present study, the role of hypoxia and HIF‑1α in the regulation of YAP in chondrocytes was investigated. The data demonstrated that hypoxia promoted the maintenance of the chondrogenic phenotype, HIF‑1α expression and YAP activation in chondrocytes in a time‑dependent manner. Hypoxia promoted YAP activation in a Hippo‑independent manner. Inhibiting the expression of HIF‑1α decreased the activation of YAP and downregulated the expression of sex‑determining region‑box 9 protein (SOX9) under hypoxic conditions, while the upregulation of HIF‑1α by cobalt chloride promoted the expression and nuclear translocation of YAP and upregulated the expression of SOX9 and collagen II chain under normoxic conditions. In addition, inhibition of YAP expression under hypoxia did not affect the expression of the HIF‑1α signaling pathway, but inhibited the up‑regulation of SOX9 expression caused by hypoxia. In addition, reoxygenation following hypoxia inhibited the activation of YAP caused by hypoxia in chondrocytes, whereas the upregulation of SOX9 and collagen II chain also appeared to be inhibited. In conclusion, the results of the present study demonstrated that hypoxia promoted YAP activation via HIF‑1α. Therefore, the HIF‑1α/YAP signaling axis may serve an important role in controlling growth plate chondrocyte differentiation and the maintenance of the chondrogenic phenotype in growth plate chondrocytes.
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http://dx.doi.org/10.3892/ijmm.2018.3921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202095PMC
December 2018

Fibroblast growth factor 18 exerts anti-osteoarthritic effects through PI3K-AKT signaling and mitochondrial fusion and fission.

Pharmacol Res 2019 01 28;139:314-324. Epub 2018 Sep 28.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address:

Osteoarthritis (OA) is a degenerative disease characterized by progressive loss of cartilage, osteophyte formation and subchondral bone sclerosis. Although some animal experiments have reported that fibroblast growth factor 18 (FGF18) attenuates cartilage degradation, the effect of FGF18 on chondrocytes and its underlying mechanism at the cellular level remain largely unknown. In this study, we found that an intra-articular injection of FGF18 attenuates cartilage degradation, increases Collagen II deposition and suppresses matrix metallopeptidase 13 (MMP13) expression in rat post-traumatic osteoarthritis (PTOA). At the cellular level, FGF18 promotes chondrocyte proliferation through PI3K-AKT signaling and migration through PI3K signaling. We found that FGF18 attenuates IL-1β-induced apoptosis, restores mitochondrial function and reduces Reactive Oxygen Species (ROS) production through PI3K-AKT signaling. Moreover, the mitochondrial fusion and fission of chondrocytes were enhanced by a short duration of treatment (within 24 h) of IL-1β and suppressed by prolonged treatment (48 h). FGF18 significantly enhances the mitochondrial fusion and fission, restoring mitochondrial function and morphology, and reduces ROS production. We also found that the FGFR1/FGFR3 ratio, which might contribute to the progression of osteoarthritis, was upregulated by IL-1β and downregulated by FGF18. To the best of our knowledge, our data demonstrated the anti-osteoarthritic effect of FGF18 at the cellular level for the first time and suggested that PI3K-AKT signaling and mitochondrial fusion and fission might play critical roles during the process. Our study proved that FGF18 might be a promising drug for the treatment of early stage osteoarthritis and is worth further study.
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http://dx.doi.org/10.1016/j.phrs.2018.09.026DOI Listing
January 2019

Downregulated microRNA-340-5p promotes proliferation and inhibits apoptosis of chondrocytes in osteoarthritis mice through inhibiting the extracellular signal-regulated kinase signaling pathway by negatively targeting the FMOD gene.

J Cell Physiol 2018 01 24;234(1):927-939. Epub 2018 Aug 24.

Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Purpose: Osteoarthritis (OA) is a degenerative joint disease that leads to the destruction of joint function. The aim of this study is to investigate the effects of microRNA-340-5p (miR-340-5p) and its target gene, FMOD, on the proliferation and apoptosis of chondrocytes in mice with OA through the extracellular signal-regulated kinase (ERK) signaling pathway.

Materials: Twenty healthy C57BL/6J mice aged 15 months with a weight of 50 ± 2 g were selected. Ten mice were treated using a unilateral knee anterior cruciate ligament transection as well as a medial meniscectomy to establish the OA model. Besides, another 10 mice were used as the control group.

Methods: A reverse transcription quantitative polymerase chain reaction and Western blot analysis methods were used to examine the expressions of related genes in cells of each group. A 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide assay and flow cytometry were also conducted to evaluate the cell function after transfection had been completed.

Results: The expressions of fibromodulin (FMOD), type II collagen (Col II), B-cell lymphoma-2 (Bcl-2), sex-determining region of Y chromosome (SRY)-related high-mobility group-box gene 9 (Sox9), and proliferating cell nuclear antigen (PCNA) were decreased, whereas the expressions of miR-340-5p, runt-related transcription factor-2 (Runx2), Bcl-2-associated X protein (Bax), and ERK1/2 were elevated in the OA mice. Downregulation of miR-340-5p and upregulation of FMOD decreased the expressions of Runx2, Bax, and ERK1/2, and cell apoptosis of chondrocytes, and increased the expressions of FMOD, Col II, Bcl-2, Sox9, and PCNA, and cell proliferation.

Conclusion: This study suggests that downregulation of miR-340-5p plays a role in promoting cell proliferation and suppressing cell apoptosis of chondrocytes in OA mice through inhibition of the ERK signaling pathway via the FMOD gene.
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http://dx.doi.org/10.1002/jcp.26921DOI Listing
January 2018

(2R,3R)Dihydromyricetin inhibits osteoclastogenesis and bone loss through scavenging LPS-induced oxidative stress and NF-κB and MAPKs pathways activating.

J Cell Biochem 2018 11 4;119(11):8981-8995. Epub 2018 Aug 4.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Osteolysis is a serious complication of several chronic inflammatory diseases and is closely associated with a local chronic inflammatory reaction with a variety of causes. However, similarities exist in the mechanisms of their pathological processes. Inflammatory factors and oxidative stress-induced nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways play a center role in bone erosion. Dihydromyricetin (DMY) is a natural compound with anti-inflammatory and antioxidative effect, which are commonly used in chronic pharyngitis and alcohol use disorders. In the current study, we identified that DMY attenuated lipopolysaccharide (LPS)-induced oxidative stress through inhibiting the production of reactive oxygen species (ROS) and nitric oxide (NO), downregulated COX-2 and iNOS, and promoted the activity of the antioxidative system by activating superoxide dismutase (SOD) and Nrf2/HO-1 pathway. To further investigate the underlying mechanism, we found that DMY inhibits osteoclast (OC) differentiation and bone resorption activity through blocking the RANKL-induced activation of the NF-κB and MAPKs signaling pathways and then downregulated c-Fos and NFATc1, which is essential for OC differentiation. Furthermore, DMY inhibited LPS-induced osteolysis in vivo. Collectively, these results indicate that DMY might be a promising prophylactic antiosteoclastic/resorptive agent in preventing or treating bone lysis diseases.
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http://dx.doi.org/10.1002/jcb.27154DOI Listing
November 2018

Inhibition of microRNA-384-5p alleviates osteoarthritis through its effects on inhibiting apoptosis of cartilage cells via the NF-κB signaling pathway by targeting SOX9.

Cancer Gene Ther 2018 12 30;25(11-12):326-338. Epub 2018 Jul 30.

Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, P.R. China.

Osteoarthritis (OA), a major cause of pain and disability, is a serious public issue worldwide. Some microRNAs (miRNAs) and SOX9 have been found to be expressed in OA. Therefore, the aim of this study is to investigate effects of microRNA-384-5p (miR-384-5p) on cartilage cell proliferation and apoptosis in mice with OA by targeting SOX9 through the NF-κB signaling pathway. First, bioinformatics was used to predict the SOX9-mediated miRNA (miR-384-5p), and dual luciferase reporter gene assay was conducted to further verify the relationship between miR-384-5p and SOX9. Then, the expression of miR-384-5p, SOX9, and NF-kB in mice modeled with OA was detected. To investigate the specific mechanism of miR-384-5p in OA, mimic and inhibitor of miR-384-5p and siRNA against SOX9 were used to transfect cartilage cells. Finally, proliferation, cell cycle, and cell apoptosis were detected using MTT assay and flow cytometry, respectively. Our results indicated that OA mice exhibited decreased expression of SOX9 and NF-kB but higher miR-384-5p expression. In addition, over-expressed miR-384-5p or silenced SOX9 could inhibit cell proliferation, and block cell cycle entry and induces apoptosis. SOX9 was a target gene of miR-384-5p. The NF-kB signaling pathway was inactivated after overexpression of miR-384-5p. Furthermore, we also observed that the effect of miR-384-5p inhibition was rescued when SOX9 was knocked down. The results support the view that inhibition of miR-384-5p could impede apoptosis and promote proliferation of cartilage cells through activating the NF-κB signaling pathway by promoting SOX9, thereby preventing the development of OA.
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http://dx.doi.org/10.1038/s41417-018-0029-yDOI Listing
December 2018

Proliferation and differentiation of rat adipose‑derived stem cells are regulated by yes‑associated protein.

Int J Mol Med 2018 Sep 18;42(3):1526-1536. Epub 2018 Jun 18.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.

Adipose‑derived stem cell (ASC)‑based therapy is a promising treatment strategy for diseases of the musculoskeletal system, as ASCs have the potential to differentiate into numerous cell lineages. However, this field has only recently been explored; therefore, a considerable amount of work is required to determine the therapeutic potential of ASCs. The mechanisms and factors associated with ASC proliferation and differentiation remain to be elucidated. In order to determine the biological properties and subsequent clinical applications of ASCs, these molecular mechanisms must be investigated. The transcriptional co‑activator yes‑associated protein (YAP), which is a major target of the Hippo signaling pathway, has been reported to serve a crucial role in stem cell proliferation and differentiation. To the best of our knowledge, the role of YAP in the proliferation and differentiation of rat ASCs (rASCs) has not yet been reported. The results of an immunofluorescence analysis revealed that subcellular distribution of YAP in rASCs was regulated by cell density and the actin cytoskeleton. Furthermore, western blot analysis demonstrated that YAP protein expression in rASCs was regulated by lysophosphatidic acid and the actin cytoskeleton. In addition, YAP activation promoted the proliferation of rASCs, whereas YAP inactivation promoted osteogenesis and inhibited adipogenesis of rASCs. In conclusion, these findings demonstrated that YAP may regulate the proliferation and differentiation of rASCs. Targeted modulation of YAP in rASCs may therefore increase the therapeutic effect of rASCs in musculoskeletal diseases.
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http://dx.doi.org/10.3892/ijmm.2018.3734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089759PMC
September 2018

Icariin doped bioactive glasses seeded with rat adipose-derived stem cells to promote bone repair via enhanced osteogenic and angiogenic activities.

Life Sci 2018 Jun 20;202:52-60. Epub 2018 Feb 20.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. Electronic address:

Aims: Cell communication between mesenchymal stem cells and blood vessel cells are crucial for bone repair. We have previously shown that the phyto-molecule icariin significantly promoted osteogenic differentiation of rat adipose-derived stem cells (ASCs). In the present study, we aimed to investigate the relationship between icariin induced osteogenic differentiation of ASCs and angiogenesis of rat endothelial progenitor cells (EPCs). Besides, we used icariin doped 45S5 Bioglass seeded with ASCs to promote bone healing in rat calvarial bone defect models.

Main Methods: The conditioned medium from undifferentiated ASCs (ASCs-CM) and icariin induced ASCs (Icariin-ASCs-CM) was obtained and the vascular endothelial growth factor (VEGF) protein secretion level was measured. The angiogenic capacity and molecular mechanism of ASC-CM and Icariin-ASCs-CM on rat EPCs was analyzed. Rat calvarial bone defect models were established and treated with scaffolds implantation. Micro-CT imaging, histological and immunohistological staining were performed on the isolated specimens at 12 weeks post-surgery.

Key Findings: VEGF protein expression was significantly increased after icariin treatment with the highest expression in the 10 M icariin group. Icariin-ASCs-CM obviously increased the angiogenesis of rat EPCs and this capacity was inhibited by a VEGF/VEGF receptor-specific binding inhibitor bevacizumab. Results of the in vivo investigations showed that all scaffolds promoted bone healing compared to the Control group. Icariin significantly improved the healing capacity of 45S5 Bioglass seeded with ASCs.

Significance: Implantation of Icariin/45S5 Bioglass seeded with rat ASCs could obviously promote both osteogenesis and angiogenesis and therefore represents an ideal candidate bone substitutes for bone repair and regeneration.
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http://dx.doi.org/10.1016/j.lfs.2018.02.026DOI Listing
June 2018

Mechano-growth factor protects against mechanical overload induced damage and promotes migration of growth plate chondrocytes through RhoA/YAP pathway.

Exp Cell Res 2018 05 20;366(2):81-91. Epub 2018 Feb 20.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address:

Epiphyseal growth plate is highly dynamic tissue which is controlled by a variety of endocrine, paracrine hormones, and by complex local signaling loops and mechanical loading. Mechano growth factor (MGF), the splice variant of the IGF-I gene, has been discovered to play important roles in tissue growth and repair. However, the effect of MGF on the growth plate remains unclear. In the present study, we found that MGF mRNA expression of growth plate chondrocytes was upregulated in response to mechanical stimuli. Treatment of MGF had no effect on growth plate chondrocytes proliferation and differentiation. But it could inhibit growth plate chondrocytes apoptosis and inflammation under mechanical overload. Moreover, both wound healing and transwell assay indicated that MGF could significantly enhance growth plate chondrocytes migration which was accompanied with YAP activation and nucleus translocation. Knockdown of YAP with YAP siRNA suppressed migration induced by MGF, indicating the essential role of YAP in MGF promoting growth plate chondrocytes migration. Furthermore, MGF promoted YAP activation through RhoA GTPase mediated cytoskeleton reorganization, RhoA inhibition using C3 toxin abrogated MGF induced YAP activation. Importantly, we found that MGF promoted focal adhesion(FA) formation and knockdown of YAP with YAP siRNA partially suppressed the activation of FA kinase, implying that YAP is associated with FA formation. In conclusion, MGF is an autocrine growth factor which is regulated by mechanical stimuli. MGF could not only protect growth plate chondrocytes against damage by mechanical overload, but also promote migration through activation of RhoA/YAP signaling axis. Most importantly, our findings indicate that MGF promote cell migration through YAP mediated FA formation to determine the FA-cytoskeleton remodeling.
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http://dx.doi.org/10.1016/j.yexcr.2018.02.021DOI Listing
May 2018

Role of IFT88 in icariin‑regulated maintenance of the chondrocyte phenotype.

Mol Med Rep 2018 Apr 25;17(4):4999-5006. Epub 2018 Jan 25.

Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.

Maintenance of the chondrocyte phenotype is crucial for cartilage repair during tissue engineering. Intraflagellar transport protein 88 (IFT88) is an essential component of primary cilia, shuttling signals along the axoneme. The hypothesis of the present study was that IFT88 could exert an important role in icariin‑regulated maintenance of the chondrocyte phenotype. To this end, the effects of icariin on proliferation and differentiation of the chondrogenic cell line, ATDC5, were explored. Icariin‑treated ATDC5 cells and primary chondrocytes expressed IFT88. Icariin has been demonstrated to aid in the maintenance of the articular cartilage phenotype in a rat model of post‑traumatic osteoarthritis (PTOA). Icariin promoted chondrocyte proliferation and expression of the chondrogenesis marker genes, COL II and SOX9, increased ciliary assembly, and upregulated IFT88 expression in a concentration‑ and time‑dependent manner. Icariin‑treated PTOA rats secreted more cartilage matrix compared with the controls. Knockdown of IFT88 expression with siRNA reduced extracellular signal‑regulated kinase (ERK) phosphorylation, and icariin upregulated IFT88 expression by promoting ERK phosphorylation. Thus, IFT88 serves a major role in icariin‑mediated maintenance of the chondrocyte phenotype, promoting ciliogenesis and IFT88 expression by increasing ERK phosphorylation. Icariin may therefore be useful for maintenance of the cartilage phenotype during tissue engineering.
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http://dx.doi.org/10.3892/mmr.2018.8486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865960PMC
April 2018

Corrigendum: Meclizine Prevents Ovariectomy-Induced Bone Loss and Inhibits Osteoclastogenesis Partially by Upregulating PXR.

Front Pharmacol 2017 11;8:991. Epub 2018 Jan 11.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

[This corrects the article on p. 693 in vol. 8, PMID: 29046637.].
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http://dx.doi.org/10.3389/fphar.2017.00991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769575PMC
January 2018

Meclizine Prevents Ovariectomy-Induced Bone Loss and Inhibits Osteoclastogenesis Partially by Upregulating PXR.

Front Pharmacol 2017 4;8:693. Epub 2017 Oct 4.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Pregnane X receptor (PXR) which belongs to the nuclear hormone receptor superfamily plays vital roles in several biological functions, especially in the inflammatory procedure. Besides that, PXR is revealed by recent studies to have essential effects on bone tissue. As an agonist of PXR, meclizine is a piperazine-derived histamine H1 antagonist, and has been frequently used for prevention and treatment of vomiting and nausea. Because osteoclastogenesis is characterized by the activation of inflammation-related signaling pathways, we speculated that meclizine may affect formation and function of osteoclast. In the present study, we explored the effect of meclizine on RANKL-induced osteoclastogenesis both and . In primary bone marrow-derived macrophages (BMMs), meclizine reduced osteoclast formation and bone resorption in a dose-dependent manner, while knockdown of PXR with siRNA partially abrogated the osteoclastogenesis inhibition of meclizine. On the one hand, at the molecular level, meclizine attenuated RANKL-induced activation of c-Fos, NFATc1, nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPKs), including ERK and p38, but not JNK. Meanwhile, meclizine reduced the expression of osteoclast-specific genes, including and . On the other hand, meclizine decreased OVX-induced bone loss by repressing osteoclast activity. In conclusion, our results indicated that meclizine inhibits osteoclastogenesis via regulation of several RANKL signaling pathways and PXR was involved in the processes. Therefore, meclizine may be considered as a novel therapeutic candidate for osteoclast-related diseases.
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http://dx.doi.org/10.3389/fphar.2017.00693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5632684PMC
October 2017

Basic fibroblast growth factor increases IFT88 expression in chondrocytes.

Mol Med Rep 2017 Nov 8;16(5):6590-6599. Epub 2017 Sep 8.

Graduate School, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.

Intraflagellar transport protein 88 (IFT88) is protein crucial for the assembly and maintenance of primary cilia in chondrocytes. Primary cilia regulate mechanical and chemical signals in chondrocytes; however, the effects of cytokines on IFT88 expression and cilia formation and maintenance remain to be elucidated. Therefore, the role of basic fibroblast growth factor (bFGF) on IFT88 expression were examined in theATDC5 murine chondrocytic line, in order to investigate the signaling pathways involved in this process. bFGF treatment upregulated IFT88 expression in a dose‑ and time‑dependent manner in ATDC5 cells. The effects of bFGF on IFT88 protein expression were suppressed in the presence of the extracellular signal‑regulated protein kinase (ERK) inhibitor PD0325901 and the FGF receptor inhibitor BGJ398. In addition, treatment with IFT88‑trageting small interfering (si)RNA downregulated the protein expression of IFT88 and ERK, thus suggesting that the ERK signaling pathway may be involved in the regulation of IFT88 expression in ATDC5 cells. bFGF treatment increased the number of ciliated ATDC5 cells and primary cultured chondrocytes. Downregulation of IFT88 expression by PD0325901, BGJ398, or IFT88‑targeting siRNA was revealed to reduce the number of ciliated cells. bFGF also upregulated the mRNA and protein expression of IFT88 in primary cultured chondrocytes. In conclusion, the findings of the present study suggested that bFGF may enhance the expression of IFT88, and promote primary cilia development, through the mitogen‑activated protein kinase/ERK‑mediated pathway in chondrocytes.
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http://dx.doi.org/10.3892/mmr.2017.7449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865803PMC
November 2017

HDAC6 inhibition suppresses chondrosarcoma by restoring the expression of primary cilia.

Oncol Rep 2017 Jul 2;38(1):229-236. Epub 2017 Jun 2.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.

Chondrosarcoma is a bone tumor characterized by the secretion of a cartilage-like extracellular matrix. It has been proved to lack extracellular sensor primary cilia. This study aimed to illustrate a feasible therapeutic method for chondrosarcoma by regulating primary cilia assembly through inhibiting histone deacetylases 6 (HDAC6) activation. In order to detect the interaction between primary cilia and HDAC6 in human chondrosarcoma, Tubastatin A and small interfering RNA (siRNA) were used to inhibit the endogenous expression of HDAC6. Cell viability test and Transwell assay were applied to evaluate the effects of malignant biological properties. Primary cilia staining and related proteins were detected. The abnormal expression of HDAC6 and cilia intraflagellar transport protein 88 (IFT88) was found in chondrosarcoma tissues. The inhibition of HDAC6 could downregulate the proliferation of chondrosarcoma cells in a concentration- and time-dependent manner and suppress the invasion capacity of tumor cells. Besides, the downregulation of HDAC6 exhibited a negative effect on the proliferation of relevant proteins but a positive effect on the primary cilia-related expression of IFT88 and acetylated α-tubulin. Primary cilia restoration could be observed after HDAC6 siRNA transfection. The Aurora A-HDAC6 cascade was involved in regulating primary cilia resorption by affecting α-tubulin deacetylation and Tubastatin A could inhibit chondrosarcoma cell growth in vivo. These results indicate that restricting HDAC6 can restore primary cilia assembly accompanied with suppressed chondrosarcoma cell proliferation and invasion capacities. Thus, promoting primary cilia restoration by targeting HDAC6 may be a feasible potential therapeutic method for chondro-sarcoma treatment.
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http://dx.doi.org/10.3892/or.2017.5694DOI Listing
July 2017

Combined anterior-posterior approach with enlarged sciatic foramen to remove sciatic notch dumbbell-shaped tumors.

J Surg Oncol 2017 Mar 30;115(4):384-389. Epub 2017 Jan 30.

Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.

Background And Objectives: To explore a new method for resecting huge sciatic notch dumbbell-shaped tumors.

Methods: Preoperative thin-slide scanning magnetic resonance images (MRI) and computerized tomography angiography (CTA) scans were conducted. The images were processed to reconstruct a 3-dimensional (3D) model. The relationship between the tumor and surrounding anatomical structures was accurately identified. By combining an anterior-posterior approach, about 1.0 × 5.0 cm c-shaped bone around the greater sciatic foramen was removed using piezosurgery osteotomy to enlarge the sciatic notch, after which retroperitoneal dumbbell-shaped tumors in the four patients were excised.

Results: Tumors in four patients were completely removed. Two patients obtain a total en bloc tumor resection; one patient was clinically determined to be a benign nerve-sheath tumor which was removed within the sciatic nerve sheath, and one patient had an extremely asymmetric tumor shape. The tumor unexpectedly split at the dumbbell isthmus across the greater sciatic foramen during blunt dissection, while both sections were completely removed.

Conclusions: The combined anterior-posterior approach with an enlarged sciatic notch is an effective method to remove sciatic notch dumbbell-shaped tumors. Compared to the reported study, it is a new method probably helpful for selected patients.
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http://dx.doi.org/10.1002/jso.24552DOI Listing
March 2017
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