Publications by authors named "Hong-In Shin"

112 Publications

Selenoprotein W ensures physiological bone remodeling by preventing hyperactivity of osteoclasts.

Nat Commun 2021 04 15;12(1):2258. Epub 2021 Apr 15.

Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine, Daegu, Korea.

Selenoproteins containing selenium in the form of selenocysteine are critical for bone remodeling. However, their underlying mechanism of action is not fully understood. Herein, we report the identification of selenoprotein W (SELENOW) through large-scale mRNA profiling of receptor activator of nuclear factor (NF)-κΒ ligand (RANKL)-induced osteoclast differentiation, as a protein that is downregulated via RANKL/RANK/tumour necrosis factor receptor-associated factor 6/p38 signaling. RNA-sequencing analysis revealed that SELENOW regulates osteoclastogenic genes. SELENOW overexpression enhances osteoclastogenesis in vitro via nuclear translocation of NF-κB and nuclear factor of activated T-cells cytoplasmic 1 mediated by 14-3-3γ, whereas its deficiency suppresses osteoclast formation. SELENOW-deficient and SELENOW-overexpressing mice exhibit high bone mass phenotype and osteoporosis, respectively. Ectopic SELENOW expression stimulates cell-cell fusion critical for osteoclast maturation as well as bone resorption. Thus, RANKL-dependent repression of SELENOW regulates osteoclast differentiation and blocks osteoporosis caused by overactive osteoclasts. These findings demonstrate a biological link between selenium and bone metabolism.
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http://dx.doi.org/10.1038/s41467-021-22565-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050258PMC
April 2021

Metabolic activities affect femur and lumbar vertebrae remodeling, and anti-resorptive risedronate disturbs femoral cortical bone remodeling.

Exp Mol Med 2021 Jan 12;53(1):103-114. Epub 2021 Jan 12.

Laboratory of Bone Metabolism and Control, Department of Microbiology, Yeungnam University College of Medicine, Daegu, 42415, Korea.

Metabolic activities are closely correlated with bone remodeling and long-term anti-resorptive bisphosphonate treatment frequently causes atypical femoral fractures through unclear mechanisms. To explore whether metabolic alterations affect bone remodeling in femurs and lumbar vertebrae and whether anti-osteoporotic bisphosphonates perturb their reconstruction, we studied three mouse strains with different fat and lean body masses (BALB/c, C57BL6, and C3H mice). These mice displayed variable physical activity, food and drink intake, energy expenditure, and respiratory quotients. Following intraperitoneal calcein injection, double calcein labeling of the femoral diaphysis, as well as serum levels of the bone-formation marker procollagen type-I N-terminal propeptide and the bone-resorption marker C-terminal telopeptide of type-I collagen, revealed increased bone turnover in mice in the following order: C3H > BALB/c ≥ C57BL6 mice. In addition, bone reconstitution in femurs was distinct from that in lumbar vertebrae in both healthy control and estrogen-deficient osteoporotic mice with metabolic perturbation, particularly in terms of femoral trabecular and cortical bone remodeling in CH3 mice. Interestingly, subcutaneous administration of bisphosphonate risedronate to C3H mice with normal femoral bone density led to enlarged femoral cortical bones with a low bone mineral density, resulting in bone fragility; however, this phenomenon was not observed in mice with ovariectomy-induced femoral cortical bone loss. Together, these results suggest that diverse metabolic activities support various forms of bone remodeling and that femur remodeling differs from lumbar vertebra remodeling. Moreover, our findings imply that the adverse effect of bisphosphonate agents on femoral cortical bone remodeling should be considered when prescribing them to osteoporotic patients.
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http://dx.doi.org/10.1038/s12276-020-00548-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080628PMC
January 2021

Sinus floor augmentation using mixture of mineralized cortical bone and cancellous bone allografts: Radiographic and histomorphometric evaluation.

J Dent Sci 2020 Sep 8;15(3):257-264. Epub 2020 Jun 8.

Department of Periodontology, School of Dentistry, Chosun University, Gwangju, Republic of Korea.

Background/purpose: Due to the pneumatization of the maxillary sinus, the sinus floor augmentation is often performed to implant placement in the maxillary posterior region. The aim was to perform radiographic and histomorphometric evaluation after placement of mixed allografts (cortical freeze-dried bone allograft [FDBA] 50%:cancellous FDBA 50%) during sinus floor augmentation.

Materials And Methods: In 37 patients, anorganic bovine bone (ABB, sites = 16), mineralized cancellous bone allograft (MCBA, sites = 15), and mixed allografts (Mixed AG, sites = 20) were placed during sinus floor elevation via the lateral approach (LSFE), at total 51 sites with residual alveolar bone height (RBH) < 5 mm. Cone-beam computed tomography images were obtained before LSFE (T0), after surgery (T1), and 6 months after surgery (T2) for radiographic analysis. After a 6-month healing period, core biopsies were harvested and histomorphometric analysis was performed.

Results: The mean augmented bone height (ABH) of ABB, MCBA, and mixed AG groups after surgery was similar (13.86 ± 4.19 mm, 13.99 ± 4.07 mm, and 14.20 ± 3.12 mm, respectively;  > 0.05). The mean ABH of ABB, MCBA, and mixed AG groups after 6 months was similar (13.72 ± 4.55 mm, 11.83 ± 3.31 mm, and 12.53 ± 2.97 mm, respectively;  > 0.05). In the ABB, MCBA, and mixed AG groups, the proportion of newly formed bone (NB) was similar (36.13 ± 10.01%, 39.26 ± 10.72%, and 31.27 ± 18.31%, respectively;  > 0.05).

Conclusion: This result demonstrated that mixed AG led to sufficient bone augmentation and histologically comparable NB formation as compared to ABB and MCBA for sinus floor augmentation.
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http://dx.doi.org/10.1016/j.jds.2020.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486514PMC
September 2020

Inhibitory effect of oolonghomobisflavan B on osteoclastogenesis by suppressing p38 MAPK activation.

Bioorg Med Chem Lett 2020 09 21;30(18):127429. Epub 2020 Jul 21.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu 41940, Republic of Korea. Electronic address:

Suppression of differentiation and/or function of osteoclasts is considered an effective therapeutic strategy for osteolytic bone diseases such as periodontitis and osteoporosis. Evidence regarding the health benefits of oolong tea consumption is accumulating, and tea polyphenols have various pharmacological properties such as anti-cancer and anti-diabetes effects. In this study, we investigated the effect of oolonghomobisflavan B (OFB), a polyphenolic compound in oolong tea, on osteoclast differentiation. OFB suppressed receptor activator of nuclear factor-κB (RANKL)-induced formation of tartate-resistant acid phosphatase-positive multinuclear cells without cytotoxicity. OFB also significantly attenuated p38 phosphorylation, which is essential for RANKL-induced osteoclastogenesis, and inhibited the expressions of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and osteoclast-specific target genes, including dendritic cell-specific transmembrane protein and cathepsin K. Our findings suggest that OFB exhibits an anti-osteoclastogenic activity by inhibiting RANKL-mediated p38 activation, which is useful for the prevention and treatment of osteolytic bone diseases.
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http://dx.doi.org/10.1016/j.bmcl.2020.127429DOI Listing
September 2020

Inhibits Multinucleated Osteoclast Formation and Prevents Estrogen-Deficient Osteoporosis.

Int J Mol Sci 2019 Dec 2;20(23). Epub 2019 Dec 2.

Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine, Daegu 42415, Korea.

Mollusks have served as important sources of human food and medicine for a long time. Raw , a freshwater bivalve of the phylum Mollusca, is used in traditional therapies in parts of Asia. However, the therapeutic effects of on bone diseases are not known. We investigated the functional roles of in osteoporotic bone diseases. inhibited the differentiation of bone marrow-derived monocytic cells into mature osteoclasts in vitro. The ovariectomized mice that received oral administration of showed improvements in both trabecular and cortical bones. This preventive activity of against bone loss was due to limited osteoclast maturation with reduced osteoclast surface extent in trabecular bone tissue. The formation of large multinucleated osteoclasts in vitro was significantly decreased in response to , consistent with the reduced expression levels of osteoclast markers and fusion-related genes, such as , , , -, , , , , and . These data suggest that inhibits osteoclast differentiation by negatively regulating the fusion of mononuclear osteoclast precursors. Thus, our data demonstrate the ability of to effectively prevent estrogen-deficient osteoporosis through inhibition of multinucleated osteoclast formation.
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http://dx.doi.org/10.3390/ijms20236076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929078PMC
December 2019

Controlling hypoxia-inducible factor-2α is critical for maintaining bone homeostasis in mice.

Bone Res 2019 13;7:14. Epub 2019 May 13.

1Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, 61186 Korea.

Pathological bone loss is caused by an imbalance between bone formation and resorption. The bone microenvironments are hypoxic, and hypoxia-inducible factor (HIF) is known to play notable roles in bone remodeling. However, the relevant functions of HIF-2α are not well understood. Here, we have shown that HIF-2α deficiency in mice enhances bone mass through its effects on the differentiation of osteoblasts and osteoclasts. In vitro analyses revealed that HIF-2α inhibits osteoblast differentiation by targeting and stimulates RANKL-induced osteoclastogenesis via regulation of . In addition, HIF-2α appears to contribute to the crosstalk between osteoblasts and osteoclasts by directly targeting RANKL in osteoprogenitor cells. Experiments performed with osteoblast- and osteoclast-specific conditional knockout mice supported a role of HIF-2α in this crosstalk. HIF-2α deficiency alleviated ovariectomy-induced bone loss in mice, and specific inhibition of HIF-2α with ZINC04179524 significantly blocked RANKL-mediated osteoclastogenesis. Collectively, our results suggest that HIF-2α functions as a catabolic regulator in bone remodeling, which is critical for the maintenance of bone homeostasis.
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http://dx.doi.org/10.1038/s41413-019-0054-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513851PMC
May 2019

Specific targeting of PKCδ suppresses osteoclast differentiation by accelerating proteolysis of membrane-bound macrophage colony-stimulating factor receptor.

Sci Rep 2019 05 7;9(1):7044. Epub 2019 May 7.

Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine, Daegu, 42415, Korea.

c-Fms is the macrophage colony-stimulating factor (M-CSF) receptor, and intracellular signalling via the M-CSF/c-Fms axis mediates both innate immunity and bone remodelling. M-CSF-induced transient proteolytic degradation of c-Fms modulates various biological functions, and protein kinase C (PKC) signalling is activated during this proteolytic process via an unknown mechanism. Notably, the role of specific PKC isoforms involved in c-Fms degradation during osteoclast differentiation is not known. Here, we observed that inactivation of PKCδ by the biochemical inhibitor rottlerin, a cell permeable peptide inhibitor, and short hairpin (sh) RNA suppresses osteoclast differentiation triggered by treatment with M-CSF and receptor activator of NF-κB ligand. Interestingly, inhibition of PKCδ by either inhibitor or gene silencing of PKCδ accelerated M-CSF-induced proteolytic degradation of membrane-bound c-Fms via both the lysosomal pathway and regulated intramembrane proteolysis (RIPping), but did not affect c-fms expression at the mRNA level. Degradation of c-Fms induced by PKCδ inactivation subsequently inhibited M-CSF-induced osteoclastogenic signals, such as extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK), p38, and Akt. Furthermore, mice administered PKCδ inhibitors into the calvaria periosteum exhibited a decrease in both osteoclast formation on the calvarial bone surface and the calvarial bone marrow cavity, which reflects osteoclastic bone resorption activity. These data suggest that M-CSF-induced PKCδ activation maintains membrane-anchored c-Fms and allows the sequential cellular events of osteoclastogenic signalling, osteoclast formation, and osteoclastic bone resorption.
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http://dx.doi.org/10.1038/s41598-019-43501-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504882PMC
May 2019

Inhibitory Effect of KP-A038 on Osteoclastogenesis and Inflammatory Bone Loss Is Associated With Downregulation of Blimp1.

Front Pharmacol 2019 10;10:367. Epub 2019 Apr 10.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Institute for Hard Tissue and Bio-tooth Regeneration, Kyungpook National University, Daegu, South Korea.

Excessive osteoclastic activity results in pathological bone resorptive diseases, such as osteoporosis, periodontitis, and rheumatoid arthritis. As imidazole-containing compounds possess extensive therapeutic potential for the management of diverse diseases, we synthesized a series of imidazole derivatives and investigated their effects on osteoclast differentiation and function. In the present study, we found that a novel imidazole derivative, KP-A038, suppressed receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis and bone-resorbing activity and attenuated lipopolysaccharide (LPS)-induced bone destruction . KP-A038 significantly inhibited the induction of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and the expression of its target genes, including tartrate-resistant acid phosphatase (), cathepsin K (), dendritic cell-specific transmembrane protein (), and matrix metallopeptidase 9 (). KP-A038 upregulated the expression of negative regulators of osteoclast differentiation, such as interferon regulatory factor-8 () and B-cell lymphoma 6 (). Consistently, KP-A038 downregulated the expression of B lymphocyte-induced maturation protein-1 (Blimp1 encoded by ), a repressor for and . Moreover, administration of KP-A038 reduced LPS-induced bone erosion by suppressing osteoclast formation . Thus, our findings suggest that KP-A038 may serve as an effective therapeutic agent for the treatment and/or prevention of bone loss in pathological bone diseases, including osteoporosis and periodontitis.
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http://dx.doi.org/10.3389/fphar.2019.00367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467953PMC
April 2019

Orthognathic surgery for patients with fibrous dysplasia involved with dentition.

Maxillofac Plast Reconstr Surg 2018 Dec 3;40(1):37. Epub 2018 Dec 3.

1Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyungpook National University, 2177 Dalgubeol-daero, Jung-gu, Daegu, 41940 Republic of Korea.

Background: Fibrous dysplasia (FD) is characterized by the replacement of normal bone by abnormal fibro-osseous connective tissue and typically treated with surgical contouring of the dysplastic bone. When dysplastic lesions involve occlusion, not only is surgical debulking needed, orthognathic surgery for correction of dentofacial deformity is mandatory. However, the long-term stability of osteotomized, dysplastic bone segments is a major concern because of insufficient screw-to-bone engagement during surgery and the risk of FD lesion re-growth.

Case Presentation: This case report reviewed two patients with non-syndromic FD that presented with maxillary occlusal canting and facial asymmetry. Le Fort I osteotomy with recontouring of the dysplastic zygomaticomaxillary region had been performed. The stability of osseous segments were favorable. However, dysplastic, newly formed bone covered the previous plate fixation site and mild bony expansion was observed, which did not influence the facial profile. Including the current cases, 15 cases of orthognathic surgery for FD with dentition have been reported in the literature.

Conclusion: The results showed that osteotomy did not appear to significantly reduce the long-term stability of the initial fixation insufficiency of the screw to the dysplastic bone. However, based on our results and those of the others, long-term follow-up and monitoring are needed, even in cases where the osteotomized segment shows stable results.
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http://dx.doi.org/10.1186/s40902-018-0176-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275155PMC
December 2018

Suppressive effect of syndecan ectodomains and N-desulfated heparins on osteoclastogenesis via direct binding to macrophage-colony stimulating factor.

Cell Death Dis 2018 11 2;9(11):1119. Epub 2018 Nov 2.

Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine, Daegu, 42415, Korea.

Syndecans, a family of cell surface heparan sulfate proteoglycans, regulate cell differentiation via binding of their heparan sulfate chains to growth factors and cytokines and play a role in tumor growth and progression, wound repair, and intestinal mucosal damage. However, the functional and mechanistic roles of syndecans in osteoclast differentiation and bone metabolism are yet unclear. Here, we demonstrated that post-translationally glycosylated ectodomains of syndecan-1 to 4 obtained from mammalian cells efficiently suppressed osteoclast differentiation compared to those obtained from Escherichia coli with no systems for glycosylation. A concomitant decrease in the expression of osteoclast markers such as nuclear factor of activated T cells 1 (NFATc1), c-Fos, and ATP6V0D2 was observed. In addition, heparan sulfate and selectively N-desulfated heparin derivatives with 2-O- and 6-O-sulfate groups and no anticoagulant activity in blood inhibited osteoclast differentiation. The inhibitory effects of syndecan ectodomains, heparan sulfate, and N-desulfated heparin derivatives on osteoclast differentiation were attributed to their direct binding to the macrophage-colony stimulating factor (M-CSF), resulting in the blocking of M-CSF-mediated downstream signals such as extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK), p38, and Akt. Furthermore, mice injected with syndecan ectodomains, heparan sulfate, and N-desulfated heparin derivatives into periosteal regions of calvaria showed reduction in the formation of tartrate-resistant acid phosphatase (TRAP)-positive mature osteoclasts on the calvarial bone surface, thereby exhibiting decreased bone resorption. Together, these results revealed a novel role of heparan sulfate chains of syndecan ectodomains in the regulation of osteoclast differentiation.
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http://dx.doi.org/10.1038/s41419-018-1167-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215006PMC
November 2018

A novel benzamide derivative protects ligature-induced alveolar bone erosion by inhibiting NFATc1-mediated osteoclastogenesis.

Toxicol Appl Pharmacol 2018 09 20;355:9-17. Epub 2018 Jun 20.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu 41940, Republic of Korea. Electronic address:

Since elevated osteoclast formation and/or activity by inhibitory responses against pathogens leads to diverse osteolytic bone diseases including periodontitis, inhibition of osteoclast differentiation and bone resorption has been a primary therapeutic strategy. In this study, we investigated the therapeutic potential of a novel benzamide-linked molecule, OCLI-070, for preventing alveolar bone loss in mice with ligature-induced experimental periodontitis. OCLI-070 inhibited osteoclast formation by acting on both early and late stages of differentiation, and attenuated the induction of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and the expression of osteoclast-specific genes. In addition, OCLI-070 significantly suppressed the formation of actin rings and resorption pits. Analysis of the inhibitory action of OCLI-070 showed that it markedly suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced extracellular signal-regulated kinase (ERK) and NF-κB signaling cascades. Moreover, OCLI-070 prevented ligature-induced alveolar bone erosion in mice by suppressing osteoclast formation. These findings demonstrate that OCLI-070 attenuated osteoclast differentiation and function as well as ligature-induced bone erosion by inhibiting RANKL-mediated ERK and NF-κB signaling pathways.
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http://dx.doi.org/10.1016/j.taap.2018.06.017DOI Listing
September 2018

MacroH2A1.2 inhibits prostate cancer-induced osteoclastogenesis through cooperation with HP1α and H1.2.

Oncogene 2018 10 20;37(43):5749-5765. Epub 2018 Jun 20.

Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA.

Osteoclasts are multinuclear bone-resorbing cells that differentiate from hematopoietic precursor cells. Prostate cancer cells frequently spread to bone and secrete soluble signaling factors to accelerate osteoclast differentiation and bone resorption. However, processes and mechanisms that govern the expression of osteoclastogenic soluble factors secreted by prostate cancer cells are largely unknown. MacroH2A (mH2A) is a histone variant that replaces canonical H2A at designated genomic loci and establishes functionally distinct chromatin regions. Here, we report that mH2A1.2, one of the mH2A isoforms, attenuates prostate cancer-induced osteoclastogenesis by maintaining the inactive state of genes encoding soluble factors in prostate cancer cells. Our functional analyses of soluble factors identify lymphotoxin beta (LTβ) as a major stimulator of osteoclastogenesis and an essential mH2A1.2 target for its anti-osteoclastogenic activity. Mechanistically, mH2A1.2 directly interacts with HP1α and H1.2 and requires them to inactivate LTβ gene in prostate cancer cells. Consistently, HP1α and H1.2 have an intrinsic ability to inhibit osteoclast differentiation in a mH2A1.2-dependent manner. Together, our data uncover a new and specific role for mH2A1.2 in modulating osteoclastogenic potential of prostate cancer cells and demonstrate how this signaling pathway can be exploited to treat osteolytic bone metastases at the molecular level.
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http://dx.doi.org/10.1038/s41388-018-0356-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309402PMC
October 2018

Inhibitory effects of methyl-3,5-di-O-caffeoyl-epi-quinate on RANKL-induced osteoclast differentiation.

Bioorg Med Chem Lett 2018 06 9;28(10):1925-1930. Epub 2018 Apr 9.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu 41940, Republic of Korea. Electronic address:

In this study, we have shown that methyl-3,5-di-O-caffeoyl-epi-quinate, a naturally occurring compound isolated from Ainsliaea acerifolia, inhibits receptor activator of nuclear factor-κB ligand (RANKL)-induced formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts and the expression of osteoclast marker genes. Methyl-3,5-di-O-caffeoyl-epi-quinate also inhibited RANKL-induced activation of p38, Akt and extracellular signal-regulated kinase (ERK) as well as the expression of nuclear factor of activated T-cell (NFATc1), the key regulator of osteoclast differentiation. Negative regulators for osteoclast differentiation was upregulated by methyl-3,5-di-O-caffeoyl-epi-quinate. Collectively, our results suggested that methyl-3,5-di-O-caffeoyl-epi-quinate suppresses osteoclast differentiation via downregulation of RANK signaling pathways and NFATc1.
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http://dx.doi.org/10.1016/j.bmcl.2018.03.072DOI Listing
June 2018

Inhibitory Effect of Purpurogallin on Osteoclast Differentiation in Vitro through the Downregulation of c-Fos and NFATc1.

Int J Mol Sci 2018 Feb 17;19(2). Epub 2018 Feb 17.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu 41940, Korea.

Purpurogallin, a benzotropolone-containing natural compound, has been reported to exhibit numerous biological and pharmacological functions, such as antioxidant, anticancer, and anti-inflammatory effects. In this study, we enzymatically synthesized purpurogallin from pyrogallol and investigated its role in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. Purpurogallin attenuated the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts from bone marrow macrophages (BMMs) without causing cytotoxicity, and suppressed upregulation of osteoclast-specific markers, including TRAP (Acp5), cathepsin K (Ctsk), and dendritic cell-specific transmembrane protein (Dcstamp). However, purpurogallin did not affect the bone resorbing function of mature osteoclasts evident by the resorption pit assay. Activation of mitogen-activated protein kinases, Akt and IkB pathways in RANK signaling were not altered by purpurogallin, whereas the expression of c-Fos and NFATc1, key transcriptional regulators in osteoclastogenesis, was dramatically inhibited by purpurogallin. Purpurogallin also significantly reduced the expression level of B lymphocyte-induced maturation protein-1 (Blimp1) gene (Prdm1). Further, downregulation of Blimp1 led to forced expression of anti-osteoclastogenic genes, including interferon regulatory factor-8 (Irf8) and B-cell lymphoma 6 (Bcl6) genes. Taken together, our data suggested that purpurogallin inhibits osteoclast differentiation via downregulation of c-Fos and NFATc1.
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http://dx.doi.org/10.3390/ijms19020601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855823PMC
February 2018

Magnesium phosphate ceramics incorporating a novel indene compound promote osteoblast differentiation in vitro and bone regeneration in vivo.

Biomaterials 2018 03 7;157:51-61. Epub 2017 Dec 7.

Department of Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University, Daegu 41940, Republic of Korea. Electronic address:

Incorporating bioactive molecules into synthetic ceramic scaffolds is challenging. In this study, to enhance bone regeneration, a magnesium phosphate (MgP) ceramic scaffold was incorporated with a novel indene compound, KR-34893. KR-34893 induced the deposition of minerals and expression of osteoblast marker genes in primary human bone marrow mesenchymal stem cells (BMSCs) and a mouse osteoblastic MC3T3-E1 cell line. Analysis of the mode of action showed that KR-34893 induced the phosphorylation of MAPK/extracellular signal-regulated kinase and extracellular signal-regulated kinase, and subsequently the expression of bone morphogenetic protein 7, accompanied by SMAD1/5/8 phosphorylation. Accordingly, KR-34893 was incorporated into an MgP scaffold prepared by 3D printing at room temperature, followed by cement reaction. KR-34893-incorporated MgP (KR-MgP) induced the expression of osteoblast differentiation marker genes in vitro. In a rat calvaria defect model, KR-MgP scaffolds enhanced bone regeneration and increased bone volume compared with MgP scaffolds, as assessed by micro-computed tomography and histological analyses. In conclusion, we developed a method for producing osteoinductive MgP scaffolds incorporating a bioactive organic compound, without high temperature sintering. The KR-MgP scaffolds enhanced osteoblast activation in vitro and bone regeneration in vivo.
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http://dx.doi.org/10.1016/j.biomaterials.2017.11.032DOI Listing
March 2018

Diphlorethohydroxycarmalol from Ishige okamurae Suppresses Osteoclast Differentiation by Downregulating the NF-κB Signaling Pathway.

Int J Mol Sci 2017 Dec 6;18(12). Epub 2017 Dec 6.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Institute for Hard Tissue and Biotooth Regeneration, Kyungpook National University, Daegu 41940, Korea.

Marine algae possess a variety of beneficial effects on human health. In this study, we investigated whether diphlorethohydroxycarmalol (DPHC), isolated from , a brown alga, suppresses receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation. DPHC significantly suppressed RANKL-induced osteoclast differentiation and macrophage-colony stimulating factor (M-CSF) expression in a dose-dependent manner. In addition, it significantly inhibited actin ring formation, the expression of osteoclast marker genes, such as tartrate-resistant acid phosphatase (TRAP), nuclear factor of activated T-cells cytoplasmic 1 (Nfatc1), cathepsin K (Ctsk), and dendritic cell-specific transmembrane protein (Dcstamp), and osteoclast-induced bone resorption. Analysis of the RANKL-mediated signaling pathway showed that the phosphorylation of both IκB and p65 was specifically inhibited by DPHC. These results suggest that DPHC substantially suppresses osteoclastogenesis by downregulating the RANK-NF-κB signaling pathway. Thus, it holds significant potential for the treatment of skeletal diseases associated with an enhanced osteoclast activity.
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http://dx.doi.org/10.3390/ijms18122635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751238PMC
December 2017

Blocking of the Ubiquitin-Proteasome System Prevents Inflammation-Induced Bone Loss by Accelerating M-CSF Receptor c-Fms Degradation in Osteoclast Differentiation.

Int J Mol Sci 2017 Sep 25;18(10). Epub 2017 Sep 25.

Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine, Daegu 42415, Korea.

Anti-osteoporotic activity of a blocker of the ubiquitin-proteasome system, bortezomib, has known to be achieved by directly opposed action in increased bone formation by osteoblasts and in decreased bone destruction by osteoclasts. However, the mechanisms underlying the proteasome blocker inhibition of osteoclast differentiation and function are not fully understood. Here, we observed that proteasome inhibitors, such as MG132 and bortezomib, in osteoclasts accelerated the degradation of c-Fms, a cognate receptor of macrophage colony-stimulating factor (M-CSF), and did not affect the amount of receptor activator of nuclear factor kappa-B (RANK), a receptor of receptor activator of nuclear factor kappa-B ligand (RANKL). c-Fms degradation induced by proteasome inhibitors was controlled by the activation of p38/tumor necrosis factor-alpha converting enzyme (TACE)-mediated regulated intramembrane proteolysis (RIPping). This was validated through the restoration of c-Fms using specific inhibitors of p38 and TACE, and a stimulation of p38-dependent TACE. In addition, c-Fms degradation by proteasome inhibition completely blocked M-CSF-mediated intrinsic signalling and led to the suppression of osteoclast differentiation and bone resorption. In a mouse model with intraperitoneal administration of lipopolysaccharide (LPS) that stimulates osteoclast formation and leads to bone loss, proteasome blockers prevented LPS-induced inflammatory bone resorption due to a decrease in the number of c-Fms-positive osteoclasts. Our study showed that accelerating c-Fms proteolysis by proteasome inhibitors may be a therapeutic option for inflammation-induced bone loss.
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http://dx.doi.org/10.3390/ijms18102054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666736PMC
September 2017

Effects of the incorporation of ε-aminocaproic acid/chitosan particles to fibrin on cementoblast differentiation and cementum regeneration.

Acta Biomater 2017 10 29;61:134-143. Epub 2017 Jul 29.

Department of Molecular Genetics, Dental Research Institute and BK21 Program, School of Dentistry, Seoul National University, Seoul, Republic of Korea; Department of Pharmacology & Dental Therapeutics, School of Dentistry, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea. Electronic address:

Cementum formation on the exposed tooth-root surface is a critical process in periodontal regeneration. Although various therapeutic approaches have been developed, regeneration of integrated and functional periodontal complexes is still wanting. Here, we found that the OCCM30 cementoblasts cultured on fibrin matrix express substantial levels of matrix proteinases, leading to the degradation of fibrin and the apoptosis of OCCM30 cells, which was reversed upon treatment with a proteinase inhibitor, ε-aminocaproic acid (ACA). Based on these findings, ACA-releasing chitosan particles (ACP) were fabricated and ACP-incorporated fibrin (fibrin-ACP) promoted the differentiation of cementoblasts in vitro, as confirmed by bio-mineralization and expressions of molecules associated with mineralization. In a periodontal defect model of beagle dogs, fibrin-ACP resulted in substantial cementum formation on the exposed root dentin in vivo, compared to fibrin-only and enamel matrix derivative (EMD) which is used clinically for periodontal regeneration. Remarkably, the fibrin-ACP developed structural integrations of the cementum-periodontal ligament-bone complex by the Sharpey's fiber insertion. In addition, fibrin-ACP promoted alveolar bone regeneration through increased bone volume of tooth roof-of-furcation defects and root coverage. Therefore, fibrin-ACP can promote cementogenesis and osteogenesis by controlling biodegradability of fibrin, implicating the feasibility of its therapeutic use to improve periodontal regeneration.

Statement Of Significance: Cementum, the mineralized layer on root dentin surfaces, functions to anchor fibrous connective tissues on tooth-root surfaces with the collagenous Sharpey's fibers integration, of which are essential for periodontal functioning restoration in the complex. Through the cementum-responsible fiber insertions on tooth-root surfaces, PDLs transmit various mechanical responses to periodontal complexes against masticatory/occlusal stimulations to support teeth. In this study, periodontal tissue regeneration was enhanced by use of modified fibrin biomaterial which significantly promoted cementogenesis within the periodontal complex with structural integration by collagenous Sharpey's fiber insertions in vivo by controlling fibrin degradation and consequent cementoblast apoptosis. Furthermore, the modified fibrin could improve repair and regeneration of tooth roof-of-furcation defects, which has spatial curvatures and geometrical difficulties and hardly regenerates periodontal tissues.
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http://dx.doi.org/10.1016/j.actbio.2017.07.039DOI Listing
October 2017

Fucoidan-induced osteogenic differentiation promotes angiogenesis by inducing vascular endothelial growth factor secretion and accelerates bone repair.

J Tissue Eng Regen Med 2018 03 4;12(3):e1311-e1324. Epub 2017 Oct 4.

Wonkwang Bone Regeneration Research Institute, Wonkwang University, Iksan, Jeonbuk, Republic of Korea.

Osteogenesis and angiogenesis, including cell-cell communication between blood vessel cells and bone cells, are essential for bone repair. Fucoidan is a chemical compound that has a variety of biological activities. It stimulates osteoblast differentiation in human mesenchymal stem cells (MSCs), which in turn induces angiogenesis. However, the mechanism by which this communication between osteoblasts and endothelial cells is mediated remains unclear. Thus, the aim of this study was to clarify the relationship between fucoidan-induced osteoblastic differentiation in MSCs and angiogenesis in endothelial cells. First, the effect was confirmed of fucoidan on osteoblast differentiation in MSCs and obtained conditioned media from these cells (Fucoidan-MSC-CM). Next, the angiogenic activity of Fucoidan-MSC-CM was investigated and it was found that it stimulated angiogenesis, demonstrated by proliferation, tube formation, migration and sprout capillary formation in human umbilical vein endothelial cells. Messenger ribonucleic acid expression and protein secretion of vascular endothelial growth factor (VEGF) were dramatically increased during fucoidan-induced osteoblast differentiation and that its angiogenic activities were reduced by a VEGF/VEGF receptor-specific binding inhibitor. Furthermore, Fucoidan-MSC-CM increased the phosphorylation of mitogen-activated protein kinase and PI3K/AKT/eNOS signalling pathway, and that its angiogenic effects were markedly suppressed by SB203580 and AKT 1/2 inhibitor. Finally, an in vivo study was conducted and it was found that fucoidan accelerated new blood vessel formation and partially promoted bone formation in a rabbit model of a calvarial bone defect. This is the first study to investigate the angiogenic effect of fucoidan-induced osteoblastic differentiation through VEGF secretion, suggesting the therapeutic potential of fucoidan for enhancing bone repair.
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http://dx.doi.org/10.1002/term.2509DOI Listing
March 2018

Effects of vascular formation during alveolar bone process morphogenesis in mice.

Histochem Cell Biol 2017 Oct 13;148(4):435-443. Epub 2017 Jun 13.

Department of Biochemistry, School of Dentistry, IHBR, Kyungpook National University, 2177 Dalgubeol-daero, Joong-gu, Daegu, 41940, Korea.

The alveolar bone process is the thickened ridge of bone that bears the teeth and is known to have dynamic functional interactions with surrounding tissues. However, the detailed morphological changes that occur during alveolar bone process development and the underlying molecular mechanisms behind this morphogenesis have not been elucidated. In this study, we examined the detailed morphological changes of the alveolar bone process during mouse development using HE and MTC staining. In addition, we evaluated the precise localization pattern of various signaling molecules involved in blood vessel formation including CD31, α-SMA, VEGF, periostin, and TGF-β. Innervation of the alveolar bone process was examined following injection of the nerve terminal dye AM1-43. The morphological and immunohistochemical data suggested that there is an intimate relationship between alveolar bone process development and blood vessel formation. To more closely examine the role of blood vessels in alveolar bone process formation, we microinjected mice with a clinically available anti-VEGF antibody, bevacizumab, at PN5 and analyzed the effects 5 days later. Compared to the control animals, anti-VEGF treated animals showed a disruption of the integration of bony tissues to form the alveolar bone process structures, which should contain the periodontal ligaments. Based on these data, we conclude that specific morphogenesis of the alveolar bone process is closely associated with blood vessel formation.
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http://dx.doi.org/10.1007/s00418-017-1584-2DOI Listing
October 2017

Human tooth-derived biomaterial as a graft substitute for hard tissue regeneration.

Regen Med 2017 04 28;12(3):263-273. Epub 2017 Mar 28.

Department of Oral Pathology & Regenerative Medicine, School of Dentistry, Kyungpook National University, Taegu 704412, South Korea.

Aim: The present study was conducted to evaluate the efficacy of human dentine grafts for new bone augmentation.

Materials & Methods: Dentine grafts (demineralized dentine matrix [DDM] and mineralized dentine matrix [MDM]) were prepared and implanted in rats. Tetracycline was administered twice. Paraffin and resin sections were prepared from the harvested grafts and stained respectively with hematoxylin and eosin (in addition to tartrate acid phosphatase for osteoclasts) and Villanueva. The new bone formation (bone thickness, mineral apposition rate and the bone formation rate) was analyzed in tetracycline-labeled resin sections.

Results & Conclusion: DDM grafts implanted in bone were better able to augment the bone compared to MDM grafts. However, both MDM and DDM failed to induce new bone in ectopic site, they could be considered as alternative autograft substitutes after protocol optimization.
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http://dx.doi.org/10.2217/rme-2016-0147DOI Listing
April 2017

The purinergic receptor P2X5 regulates inflammasome activity and hyper-multinucleation of murine osteoclasts.

Sci Rep 2017 03 15;7(1):196. Epub 2017 Mar 15.

Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.

Excessive bone resorption by osteoclasts (OCs) can result in serious clinical outcomes, including bone loss that may weaken skeletal or periodontal strength. Proper bone homeostasis and skeletal strength are maintained by balancing OC function with the bone-forming function of osteoblasts. Unfortunately, current treatments that broadly inhibit OC differentiation or function may also interfere with coupled bone formation. We therefore identified a factor, the purinergic receptor P2X5 that is highly expressed during the OC maturation phase, and which we show here plays no apparent role in early bone development and homeostasis, but which is required for osteoclast-mediated inflammatory bone loss and hyper-multinucleation of OCs. We further demonstrate that P2X5 is required for ATP-mediated inflammasome activation and IL-1β production by OCs, and that P2X5-deficient OC maturation is rescued in vitro by addition of exogenous IL-1β. These findings identify a mechanism by which OCs react to inflammatory stimuli, and may identify purinergic signaling as a therapeutic target for bone loss-related inflammatory conditions.
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http://dx.doi.org/10.1038/s41598-017-00139-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427844PMC
March 2017

Afatinib ameliorates osteoclast differentiation and function through downregulation of RANK signaling pathways.

BMB Rep 2017 Mar;50(3):150-155

Departments of Oral Pathology and Regenerative Medicine, Kyungpook National University, Daegu 41940, Korea.

Non-small-cell lung cancer (NSCLC) is the third most common cancer that spreads to the bone, resulting in osteolytic lesions caused by hyperactivation of osteoclasts. Activating mutations in epidermal growth factor receptor-tyrosine kinase (EGF-TK) are frequently associated with NSCLC, and afatinib is a first-line therapeutic drug, irreversibly targeting EGF-TK. However, the effects of afatinib on osteoclast differentiation and activation as well as the underlying mechanism remain unclear. In this study, afatinib significantly suppressed receptor activator of nuclear factor κB (RANK) ligand (RANKL)-induced osteoclast formation in bone marrow macrophages (BMMs). Consistently, afatinib inhibited the expression of osteoclast marker genes, whereas, it upregulated the expression of negative modulator genes. The bone resorbing activity of osteoclasts was also abrogated by afatinib. In addition, afatinib significantly inhibited RANKL-mediated Akt/protein kinase B and c-Jun N-terminal kinase phosphorylation. These results suggest that afatinib substantially suppresses osteoclastogenesis by downregulating RANK signaling pathways, and thus may reduce osteolysis after bone metastasis. [BMB Reports 2017; 50(3): 150-155].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422028PMC
http://dx.doi.org/10.5483/bmbrep.2017.50.3.223DOI Listing
March 2017

OCLI-023, a Novel Pyrimidine Compound, Suppresses Osteoclastogenesis In Vitro and Alveolar Bone Resorption In Vivo.

PLoS One 2017 13;12(1):e0170159. Epub 2017 Jan 13.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu, Republic of Korea.

An abnormal increase in osteoclast differentiation and activation results in various bone-resorptive diseases, including periodontitis, rheumatoid arthritis, and osteoporosis. Chemical compounds containing pyrimidine ring have been shown to regulate a variety of biological processes. Therefore, in order to identify an antiresorptive agent, we synthesized a series of pyrimidine ring-containing chemical compounds, and found that OCLI-023 suppressed the differentiation and activation of osteoclasts in vitro. OCLI-023 directly inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced differentiation of bone marrow macrophages into osteoclasts, without a cytotoxic response. OCLI-023 also downregulated the RANKL-induced mRNA expression of osteoclast markers as well as inhibited the formation of actin rings and resorption pits. OCLI-023 attenuated the RANKL-induced activation of c-Jun N-terminal kinase and nuclear factor kappa-light-chain-enhancer of activated B cell signaling pathways. In a mouse model of periodontitis, ligature induced an increase of distance between cementoenamel junction (CEJ) and alveolar bone crest (ABC) in the second molar, and OCLI-023 significantly reduced it. Histological analysis showed ligature-induced increase of osteoclast numbers was also significantly reduced by OCLI-023. These data demonstrated the inhibitory effect of OCLI-023 on osteoclast differentiation and activity of osteoclasts in vitro, as well as on ligature-induced bone loss in vivo, and OCLI-023 can be proposed as a novel anti-resorptive compound.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170159PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234796PMC
August 2017

Involvement of PI3K and PKA pathways in mouse tongue epithelial differentiation.

Acta Histochem 2017 Jan 8;119(1):92-98. Epub 2016 Dec 8.

Department of Biochemistry, School of Dentistry, IHBR, Kyungpook National University, Daegu, South Korea. Electronic address:

In mice, tongue epithelial differentiation is mainly regulated by the interactions among various signalling molecules including Fgf signalling pathways. However, the subsequent signalling modulations for epithelial maturation, initiated by Fgf signalling, remain to be elucidated. Therefore, we employed an in vitro tongue organ cultivation system along with the applications of various pharmacological inhibitors against the intracellular signalling molecules of Fgf signalling pathways, including H89, LY294002, PD98059, and U0126. Following treatments with LY294002 and H89, inhibitors for PI3K and PKA, respectively, the decreased thickness of the tongue epithelium was observed along with the alteration in cell proliferative and apoptotic patterns. Meanwhile, cultivated tongues treated with MEK inhibitor U0126 or PD98059 showed significantly decreased cell proliferation in the tongue epithelium and the mesenchyme. Based on these results, we suggest that the tongue epithelium is differentiated into multiple epithelial cell layers via the PI3K and PKA pathways in tissue-specific manner during the epithelial-mesenchymal interactions.
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http://dx.doi.org/10.1016/j.acthis.2016.11.013DOI Listing
January 2017

BST2 Mediates Osteoblast Differentiation via the BMP2 Signaling Pathway in Human Alveolar-Derived Bone Marrow Stromal Cells.

PLoS One 2016 30;11(6):e0158481. Epub 2016 Jun 30.

Department of Periodontology, School of Dentistry, Wonkwang University, Iksan, Korea.

The molecular mechanisms controlling the differentiation of bone marrow stromal stem cells into osteoblasts remain largely unknown. In this study, we investigated whether bone marrow stromal antigen 2 (BST2) influences differentiation toward the osteoblasts lineage. BST2 mRNA expression in human alveolar-derived bone marrow stromal cells (hAD-BMSCs) increased during differentiation into osteoblasts. hAD-BMSCs differentiation into osteoblasts and the mRNA expression of the bone-specific markers alkaline phosphatase, collagen type α 1, bone sialoprotein, osteocalcin, and osterix were reduced by BST2 knockdown using siRNA. Furthermore, BST2 knockdown in hAD-BMSCs resulted in decreased RUNX2 mRNA and protein expression. We hypothesized that BST2 is involved in differentiation of into osteoblasts via the BMP2 signaling pathway. Accordingly, we evaluated the mRNA expression levels of BMP2, BMP receptors (BMPR1 and 2), and the downstream signaling molecules SMAD1, SMAD4, and p-SMAD1/5/8 in BST2 knockdown cells. BMP2 expression following the induction of differentiation was significantly lower in BST2 knockdown cells than in cells treated with a non-targeting control siRNA. Similar results were found for the knockdown of the BMP2 receptor- BMPR1A. We also identified significantly lower expression of SMAD1, SMAD4, and p-SMAD1/5/8 in the BST2 knockdown cells than control cells. Our data provide the first evidence that BST2 is involved in the osteogenic differentiation of bone marrow stromal cells via the regulation of the BMP2 signaling pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158481PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928849PMC
July 2017

Sirt6 cooperates with Blimp1 to positively regulate osteoclast differentiation.

Sci Rep 2016 05 18;6:26186. Epub 2016 May 18.

Department of Life Science, Ewha Womans University, Seoul 120-750, Korea.

Global deletion of the gene encoding a nuclear histone deacetylase sirtuin 6 (Sirt6) in mice leads to osteopenia with a low bone turnover due to impaired bone formation. But whether Sirt6 regulates osteoclast differentiation is less clear. Here we show that Sirt6 functions as a transcriptional regulator to directly repress anti-osteoclastogenic gene expression. Targeted ablation of Sirt6 in hematopoietic cells including osteoclast precursors resulted in increased bone volume caused by a decreased number of osteoclasts. Overexpression of Sirt6 led to an increase in osteoclast formation, and Sirt6-deficient osteoclast precursor cells did not undergo osteoclast differentiation efficiently. Moreover, we showed that Sirt6, induced by RANKL-dependent NFATc1 expression, forms a complex with B lymphocyte-induced maturation protein-1 (Blimp1) to negatively regulate expression of anti-osteoclastogenic gene such as Mafb. These findings identify Sirt6 as a novel regulator of osteoclastogenesis by acting as a transcriptional repressor.
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http://dx.doi.org/10.1038/srep26186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870620PMC
May 2016

Extracellular calcium-binding peptide-modified ceramics stimulate regeneration of calvarial bone defects.

Tissue Eng Regen Med 2016 Feb 28;13(1):57-65. Epub 2015 Dec 28.

1Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu, Korea.

Secreted protein, acidic, cysteine-rich (SPARC)-related modular calcium binding 1 (SMOC1) has been implicated in the regulation of osteogenic differentiation of human bone marrow mesenchymal stem cells (BMSCs). In this study, we found that a peptide (16 amino acids in length), which is located in the extracellular calcium (EC) binding domain of SMOC1, stimulated osteogenic differentiation of human BMSCs and calvarial bone regeneration . Treatment of BMSCs with SMOC1-EC peptide significantly stimulated their mineralization in a dose-dependent manner without changing their rate of proliferation. The expression of osteogenic differentiation marker genes, including type 1 collagen and osteocalcin, also increased in a dose-dependent manner. To examine the effect of the SMOC1-EC peptide on bone formation , the peptide was covalently immobilized onto hydroxyapatite/β-tricalcium phosphate (HA/β-TCP) particles. X-ray photoelectron spectroscopy analysis showed that the peptide was successfully immobilized onto the surface of HA/β-TCP. Implantation of the SMOC1-EC peptide-immobilized HA/β-TCP particles into mouse calvarial defects and subsequent analyses using microcomputed tomography and histology showed significant bone regeneration compared with that of calvarial defects implanted with unmodified HA/β-TCP particles. Collectively, our data suggest that a peptide derived from the EC domain of SMOC1 induces osteogenic differentiation of human BMSCs and efficiently enhances bone regeneration .
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http://dx.doi.org/10.1007/s13770-015-9066-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170992PMC
February 2016

Inhibitory Effects of KP-A159, a Thiazolopyridine Derivative, on Osteoclast Differentiation, Function, and Inflammatory Bone Loss via Suppression of RANKL-Induced MAP Kinase Signaling Pathway.

PLoS One 2015 4;10(11):e0142201. Epub 2015 Nov 4.

Department of Oral Pathology and Regenerative Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu, Republic of Korea.

Abnormally elevated formation and activation of osteoclasts are primary causes for a majority of skeletal diseases. In this study, we found that KP-A159, a newly synthesized thiazolopyridine derivative, inhibited osteoclast differentiation and function in vitro, and inflammatory bone loss in vivo. KP-A159 did not cause a cytotoxic response in bone marrow macrophages (BMMs), but significantly inhibited the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts induced by macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). KP-A159 also dramatically inhibited the expression of marker genes related to osteoclast differentiation, including TRAP (Acp5), cathepsin K (Ctsk), dendritic cell-specific transmembrane protein (Dcstamp), matrix metallopeptidase 9 (Mmp9), and nuclear factor of activated T-cells, cytoplasmic 1 (Nfatc1). Moreover, actin ring and resorption pit formation were inhibited by KP-A159. Analysis of the signaling pathway involved showed that KP-A159 inhibited RANKL-induced activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and mitogen-activated protein kinase kinase1/2 (MEK1/2). In a mouse inflammatory bone loss model, KP-A159 significantly rescued lipopolysaccharide (LPS)-induced bone loss by suppressing osteoclast numbers. Therefore, KP-A159 targets osteoclasts, and may be a potential candidate compound for prevention and/or treatment of inflammatory bone loss.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142201PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633183PMC
June 2016

The role of APCDD1 in epithelial rearrangement in tooth morphogenesis.

Histochem Cell Biol 2015 Oct 14;144(4):377-87. Epub 2015 Jul 14.

Department of Biochemistry, School of Dentistry, IHBR, Kyungpook National University, 2177 Dalgubeol-daero, Joong-gu, Daegu, 700-412, Korea.

Adenomatosis polyposis coli downregulated 1 (APCDD1), a negative regulator of Wnt signaling, was examined to understand detailed mechanisms underlying Wnt signaling tooth development. In situ hybridization showed that Apcdd1 was expressed in the condensed mesenchyme at the bud stage, and in the inner enamel epithelium (IEE), including enamel knot (EK) at the cap stage. In vitro organ cultivation by using Apcdd1 antisense oligodeoxynucleotides was performed at E13.5 for 2 days to define the developmental functions of APCDD1 during tooth development. Analysis of histogenesis and cellular events such as cell adhesion, proliferation, apoptosis and epithelial rearrangement after Apcdd1 knockdown showed altered morphogenesis of the tooth germ with decreased cell proliferation and altered localization of cell adhesion molecules. Actin filament staining and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) labeling of IEE cells showed that Apcdd1 knockdown enhanced epithelial rearrangement in the IEE and EK. To understand the precise signaling regulations of Apcdd1, we evaluated the altered expression patterns of signaling molecules, related with Wnt and enamel knot signalings using RT-qPCR. Tooth germs at cap stage were transplanted into the kidney capsules and were allowed to develop into calcified teeth for 3 weeks. Apcdd1 knockdown increased the number of ectopic cusps on the mesial side of the tooth. Our results suggested that APCDD1 modulates the gene expression of Wnt- and EK-related signaling molecules at the cap stage of tooth development, and is involved in tooth cusp patterning by modulating the epithelial rearrangement in the IEE.
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http://dx.doi.org/10.1007/s00418-015-1345-zDOI Listing
October 2015
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