Publications by authors named "Shuying Yang"

132 Publications

FIGNL1 Inhibits Non-homologous Chromosome Association and Crossover Formation.

Front Plant Sci 2022 11;13:945893. Epub 2022 Jul 11.

Jiangsu Co-Innovation Center for Modern Production Technology of Grain Crops, Yangzhou University, Yangzhou, China.

Meiotic crossovers (COs) not only generate genetic diversity but also ensure the accuracy of homologous chromosome segregation. Here, we identified FIGNL1 as a new inhibitor for extra crossover formation in rice. The mutant displays abnormal interactions between non-homologous chromosomes at diakinesis, and chromosome bridges and fragmentation at subsequent stages of meiosis, but shows normal homologous chromosome pairing and synapsis during early prophase I. FIGNL1 participates in homologous chromosome recombination and functions downstream of DMC1. Mutation of increases the number of bivalents in mutants, but does not change the number of HEI10 foci, indicating that FIGNL1 functions in limiting class II CO formation. FIGNL1 interacts with MEICA1, and colocalizes with MEICA1 in a dynamic pattern as punctate foci located between two linear homologous chromosomes. The localization of FIGNL1 depends on ZEP1-mediated assembly of the synaptonemal complex. Based on these results, we propose that FIGNL1 inhibits non-homologous chromosome interaction and CO formation during rice meiosis.
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http://dx.doi.org/10.3389/fpls.2022.945893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9310568PMC
July 2022

Macrophage RGS12 contributes to osteoarthritis pathogenesis through enhancing the ubiquitination.

Genes Dis 2022 Sep 26;9(5):1357-1367. Epub 2021 Aug 26.

Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Ubiquitination has important functions in osteoarthritis (OA), yet the mechanism remains unclear. Here, we identify the regulator of G protein signaling 12 (RGS12) in macrophages, which promotes the association between ubiquitin and IκB during inflammation. We also find that RGS12 promotes the degradation of IκB through enhancing the ubiquitination whereas the process can be inhibited by MG132. Moreover, the increased ubiquitination further inhibits the expression of MTAP, which can indirectly activate the phosphorylation of IκB. Finally, due to the degradation of IκB, the NF-κB translocates into the nucleus and further promotes the gene expression of cytokines such as , , and during inflammation. Importantly, RGS12 deficiency prevents ubiquitination and inflammation in surgically or chemically induced OA. We conclude that the lack of RGS12 in macrophages interferes with the ubiquitination and degradation of IκB, thereby preventing inflammation and cartilage damage. Our results provide evidence for the relevance of RGS12 in promoting inflammation and regulating immune signaling.
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http://dx.doi.org/10.1016/j.gendis.2021.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9293709PMC
September 2022

Trp53 controls chondrogenesis and endochondral ossification by negative regulation of TAZ activity and stability via β-TrCP-mediated ubiquitination.

Cell Death Discov 2022 Jul 12;8(1):317. Epub 2022 Jul 12.

Department of Basic & Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Transformation-related protein 53 (Trp53) is a critical regulator of cell fate determination by controlling cell proliferation and differentiation. Ablation of Trp53 signaling in osteoblast lineages significantly promotes osteogenesis, bone formation, and bone remodeling. However, how Trp53 regulates chondrogenesis and endochondral bone formation is undefined. In this study, we found that Trp53 expression gradually decreased in tibia growth plates during embryonic development in vivo and during chondrogenesis in vitro. By deleting Trp53 in chondrocyte lineage using Col2-Cre transgenic line, we found that loss of Trp53 in chondrocytes significantly increased growth plate growth and bone formation by increasing chondrocyte proliferation, matrix production and maturation, and bone dynamic formation rate. Mechanistically, our data revealed loss of Trp53 significantly promoted TAZ transcriptional activity through inhibition of TAZ phosphorylation and nuclear translocation, whereas its activity was pronouncedly inhibited after forced expression of Trp53. Furthermore, Co-IP data demonstrated that Trp53 associated with TAZ. Moreover, Trp53 decreased the stability of TAZ protein and promoted its degradation through β-TrCP-mediated ubiquitination. Ablation of TAZ in Col2-Cre;Trp53 mice rescued the phenotypes of enhanced chondrogenesis and bone formation caused by Trp53 deletion. Collectively, this study revealed that Trp53 modulates chondrogenesis and endochondral ossification through negative regulation of TAZ activity and stability, suggesting that targeting Trp53 signaling may be a potential strategy for fracture healing, heterotopic ossification, arthritis, and other bone diseases.
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http://dx.doi.org/10.1038/s41420-022-01105-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279315PMC
July 2022

Mice with Trp53 and Rb1 deficiency in chondrocytes spontaneously develop chondrosarcoma via overactivation of YAP signaling.

Cell Death Dis 2022 Jun 27;13(6):570. Epub 2022 Jun 27.

Department of Basic & Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Chondrosarcoma (CHS) is a rare type of soft sarcoma with increased production of cartilage matrix arising from soft bone tissues. Currently, surgical resection is the primary clinical treatment for chondrosarcoma due to the poor response to radiotherapy and chemotherapy. However, the therapeutic effect is not satisfactory due to the higher local recurrence rate. Thus, management and elucidation of the pathological mechanism of chondrosarcoma remain an ongoing challenge, and the development of effective chondrosarcoma mouse models and treatment options are urgently needed. Here, we generated a new transgenic chondrosarcoma model by double conditional deletions of Trp53 and Rb1 in chondrocyte lineage which spontaneously caused spinal chondrosarcoma and lung metastasis. Bioinformatic analysis of the human soft sarcoma database showed that Trp53 and Rb1 genes had higher mutations, reaching up to approximately 33.5% and 8.7%, respectively. Additionally, Trp53 and Rb1 signatures were decreased in the human and mouse chondrosarcoma tissues. Mechanistically, we found that YAP expression and activity were significantly increased in mouse Col2-Cre;Trp53/Rb1 chondrosarcoma tissues compared to the adjacent normal cartilage. Knockdown of YAP in primary chondrosarcoma cells significantly inhibited chondrosarcoma proliferation, invasion, and tumorsphere formation. Chondrocyte lineage ablation of YAP delayed chondrosarcoma progression and lung metastasis in Col2-Cre;Trp53/Rb1 mice. Moreover, we found that metformin served as a YAP inhibitor, which bound to the activity area of YAP protein, and inhibited chondrosarcoma cell proliferation, migration, invasion, and progression in vitro and significantly suppressed chondrosarcoma formation in vivo. Collectively, this study identifies the inhibition of YAP may be an effective therapeutic strategy for the treatment of chondrosarcoma.
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http://dx.doi.org/10.1038/s41419-022-04916-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9237030PMC
June 2022

IFT20 governs mesenchymal stem cell fate through positively regulating TGF-β-Smad2/3-Glut1 signaling mediated glucose metabolism.

Redox Biol 2022 08 20;54:102373. Epub 2022 Jun 20.

Department of Basic & Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; The Penn Center for Musculoskeletal Disorders, School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. Electronic address:

Aberrant lineage allocation of mesenchymal stem cells (MSCs) could cause bone marrow osteoblast-adipocyte imbalance, and glucose as an important nutrient is required for the maintenance of the MSCs' fate and function. Intraflagellar transport 20 (IFT20) is one of the IFT complex B protein which regulates osteoblast differentiation, and bone formation, but how IFT20 regulates MSCs' fate remains undefined. Here, we demonstrated that IFT20 controls MSC lineage allocation through regulating glucose metabolism during skeletal development. IFT20 deficiency in the early stage of MSCs caused significantly shortened limbs, decreased bone mass and significant increase in marrow fat. However, deletion of IFT20 in the later stage of MSCs and osteocytes just slightly decreased bone mass and bone growth and increased marrow fat. Additionally, we found that loss of IFT20 in MSCs promotes adipocyte formation, which enhances RANKL expression and bone resorption. Conversely, ablation of IFT20 in adipocytes reversed these phenotypes. Mechanistically, loss of IFT20 in MSCs significantly decreased glucose tolerance and suppressed glucose uptake and lactate and ATP production. Moreover, loss of IFT20 significantly decreased the activity of TGF-β-Smad2/3 signaling and reduced the binding activity of Smad2/3 to Glut1 promoter to downregulate Glut1 expression. These findings indicate that IFT20 plays essential roles for preventing MSC lineage allocation into adipocytes through TGF-β-Smad2/3-Glut1 axis.
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http://dx.doi.org/10.1016/j.redox.2022.102373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9243161PMC
August 2022

Type II collagen-positive progenitors are important stem cells in controlling skeletal development and vascular formation.

Bone Res 2022 Jun 23;10(1):46. Epub 2022 Jun 23.

Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Type II collagen-positive (Col2) cells have been reported as skeletal stem cells (SSCs), but the contribution of Col2 progenitors to skeletal development both prenatally and postnatally during aging remains unclear. To address this question, we generated new mouse models with ablation of Col2 cells at either the embryonic or postnatal stages. The embryonic ablation of Col2 progenitors resulted in the death of newborn mice due to a decrease in skeletal blood vessels, loss of all vertebral bones and absence of most other bones except part of the craniofacial bone, the clavicle bone and a small piece of the long bone and ribs, which suggested that intramembranous ossification is involved in long bone development but does not participate in spine development. The postnatal ablation of Col2 cells resulted in mouse growth retardation and a collagenopathy phenotype. Lineage tracing experiments with embryonic or postnatal mice revealed that Col2 progenitors occurred predominantly in the growth plate (GP) and articular cartilage, but a limited number of Col2 cells were detected in the bone marrow. Moreover, the number and differentiation ability of Col2 progenitors in the long bone and knee joints decreased with increasing age. The fate-mapping study further revealed Col2 lineage cells contributed to, in addition to osteoblasts and chondrocytes, CD31 blood vessels in both the calvarial bone and long bone. Specifically, almost all blood vessels in calvarial bone and 25.4% of blood vessels in long bone were Col2 lineage cells. However, during fracture healing, 95.5% of CD31 blood vessels in long bone were Col2 lineage cells. In vitro studies further confirmed that Col2 progenitors from calvarial bone and GP could form CD31 vascular lumens. Thus, this study provides the first demonstration that intramembranous ossification is involved in long bone and rib development but not spine development. Col2 progenitors contribute to CD31 skeletal blood vessel formation, but the percentage differs between long bone and skull bone. The number and differentiation ability of Col2 progenitors decreases with increasing age.
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http://dx.doi.org/10.1038/s41413-022-00214-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9226163PMC
June 2022

IFT80 negatively regulates osteoclast differentiation via association with Cbl-b to disrupt TRAF6 stabilization and activation.

Proc Natl Acad Sci U S A 2022 06 21;119(26):e2201490119. Epub 2022 Jun 21.

Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Excess bone loss due to increased osteoclastogenesis is a significant clinical problem. Intraflagellar transport (IFT) proteins have been reported to regulate cell growth and differentiation. The role of IFT80, an IFT complex B protein, in osteoclasts (OCs) is completely unknown. Here, we demonstrate that deletion of IFT80 in the myeloid lineage led to increased OC formation and activity accompanied by severe bone loss in mice. IFT80 regulated OC formation by associating with Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) to promote protein stabilization and proteasomal degradation of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6). IFT80 knockdown resulted in increased ubiquitination of Cbl-b and higher TRAF6 levels, thereby hyperactivating the receptor activator of nuclear factor-κβ (NF-κβ) ligand (RANKL) signaling axis and increased OC formation. Ectopic overexpression of IFT80 rescued osteolysis in a calvarial model of bone loss. We have thus identified a negative function of IFT80 in OCs.
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http://dx.doi.org/10.1073/pnas.2201490119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9245634PMC
June 2022

Deletion of Trp53 and Rb1 in Ctsk-expressing cells drives osteosarcoma progression by activating glucose metabolism and YAP signaling.

MedComm (2020) 2022 Jun 22;3(2):e131. Epub 2022 Apr 22.

Department of Basic & Translational Sciences School of Dental Medicine University of Pennsylvania Philadelphia Pennsylvania USA.

Glucose metabolism reprogramming is a critical factor in the progression of multiple cancers and is directly regulated by many tumor suppressors. However, how glucose metabolism regulates osteosarcoma development and progression is largely unknown. Cathepsin K (Ctsk) has been reported to express in chondroprogenitor cells and stem cells besides osteoclasts. Moreover, mutations in the tumor suppressors transformation-related protein 53 (Trp53) and retinoblastoma protein (Rb1) are evident in approximately 50%-70% of human osteosarcoma. To understand how deletion of Trp53 and Rb1 in Ctsk-expressing cells drives tumorigenesis, we generated the Ctsk-Cre;Trp53/Rb1 mouse model. Our data revealed that those mice developed osteosarcoma without formation of tumor in osteoclast lineage. The level of cortical bone destruction was gradually increased in parallel to the osteosarcoma progression rate. Through mechanistic studies, we found that loss of Trp53/Rb1 in Ctsk-expressing cells significantly elevated Yes-associated protein (YAP) expression and activity. YAP/TEAD1 complex binds to the glucose transporter 1 () promoter to upregulate Glut1 expression. Upregulated expression led to overactive glucose metabolism, increasing osteosarcoma progression. Ablation of YAP signaling inhibited energy metabolism and delayed osteosarcoma progression in Ctsk-Cre;Trp53/Rb1 mice. Collectively, these findings provide proof of principle that inhibition of YAP activity may be a potential strategy for osteosarcoma treatment.
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http://dx.doi.org/10.1002/mco2.131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9026232PMC
June 2022

Effect of Regulator of G Protein Signaling Proteins on Bone.

Front Endocrinol (Lausanne) 2022 29;13:842421. Epub 2022 Apr 29.

Department of Basic and Translational Sciences, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States.

Regulator of G protein signaling (RGS) proteins are critical negative molecules of G protein-coupled receptor (GPCR) signaling, which mediates a variety of biological processes in bone homeostasis and diseases. The RGS proteins are divided into nine subfamilies with a conserved RGS domain which plays an important role in regulating the GTPase activity. Mutations of some RGS proteins change bone development and/or metabolism, causing osteopathy. In this review, we summarize the recent findings of RGS proteins in regulating osteoblasts, chondrocytes, and osteoclasts. We also highlight the impacts of RGS on bone development, bone remodeling, and bone-related diseases. Those studies demonstrate that RGS proteins might be potential drug targets for bone diseases.
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http://dx.doi.org/10.3389/fendo.2022.842421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9098968PMC
May 2022

Verteporfin Inhibits the Progression of Spontaneous Osteosarcoma Caused by Trp53 and Rb1 Deficiency in Ctsk-Expressing Cells via Impeding Hippo Pathway.

Cells 2022 04 16;11(8). Epub 2022 Apr 16.

Department of Basic & Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Osteosarcoma is the most common primary malignancy of bone in children and adolescents. Others and our previous studies have shown that Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) as core components of the Hippo pathway are crucial regulators of osteosarcoma formation and progression. Recent studies demonstrated that verteporfin (VP) is an inhibitor of YAP/TAZ signaling in xenograft osteosarcoma. However, whether VP can inhibit primary osteosarcoma in mice is unknown. Mutations of Trp53 and Rb1 occur in approximately 50~70% of human osteosarcoma. In this study, we successfully generated the Ctsk-Cre;Trp53/Rb1 mice in which Trp53/Rb1 was ablated in Ctsk-expressing cells and found that Ctsk-Cre;Trp53/Rb1 mice spontaneously developed osteosarcoma with increased expansive osteoid lesions in the cortical bone with aging. Loss of Trp53/Rb1 in Ctsk-expressing cells significantly promoted the expression and nuclear translocation of YAP/TAZ. Micro-CT results showed that inhibition of YAP/TAZ by VP delays osteosarcoma progression and protected against bone erosion in Ctsk-Cre;Trp53/Rb1 mice. Importantly, the Kaplan-Meier survival curves displayed a significantly longer survival rate after VP treatment in Ctsk-Cre;Trp53/Rb1 mice compared to non-injected groups. In vitro studies further showed that VP inhibited the proliferation, migration and invasion in Trp53/Rb1-mutant Ctsk-expressing cells. Moreover, the results from promoter luciferase activity analysis showed that the transcriptional activity of YAP/TAZ was significantly increased in osteosarcoma tissue from Ctsk-Cre;Trp53/Rb1 mice, which was attenuated by VP treatment. Overall, these findings suggest that targeting Hippo pathway by VP may be a potential therapeutic strategy for osteosarcoma.
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http://dx.doi.org/10.3390/cells11081361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9031376PMC
April 2022

An In Vitro Study of Fluid Contaminations Influences on Reverse Torque Values of Implant-Abutment Connections.

Biomed Res Int 2022 8;2022:4111710. Epub 2022 Mar 8.

Department of Stomatology, Xi'an Children's Hospital, Affiliated Children's Hospital, Xi'an Jiaotong University, 710003, China.

Purpose: To examine the effects of fluid contamination on the reverse torque value (RTV) of abutment screws. 484 titanium fixtures were mounted into the stainless-steel holders.

Methods: 11 groups (44 specimens in each group) of implants were mounted in acrylic resin. Ten groups of fixture screw holes were contaminated with chlorhexidine, saliva, blood, fluoride, or combination groups, and one group served as a control without contamination. To simulate the oral environment, samples were subjected to thermal cycling and cyclic loading.

Results: The RTV means were less than the initial torque in both control and contamination groups. The maximum RTV mean was observed in the fluoride group (26.00 ± 1.02 Ncm). In other groups, this rate for control, blood, saliva, and chlorhexidine groups were 18.00 ± 1.78 Ncm, 22.12 ± 1.56 Ncm, 21.56 ± 1.43 Ncm, and 21.89 ± 1.02 Ncm, respectively. In combination groups, the maximum RTV mean was observed in the saliva+CHX group (23.89 ± 1.92 Ncm). In other combination groups, this rate for the blood+CHX, blood+saliva, saliva+fluoride, fluoride+CHX, and fluoride+blood groups were 22.56 ± 1.73 Ncm, 22.00 ± 1.54 Ncm, 20.11 ± 1.58 Ncm, 23.51 ± 1.19 Ncm, 21.02 ± 1.38 Ncm, and 20.11 ± 1.58 Ncm, respectively. The RTV was statistically significant ( < 0.05) for the contamination groups (except saliva) and combination groups compared to the control group. There is no statistically significant difference ( > 0.05) between the reverse torque value mean of the blood and saliva groups and between that of the fluoride and chlorhexidine groups.

Conclusion: Implant-abutment specimens are suggested to be placed in a saliva environment and should be subjected to cyclic loading.
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http://dx.doi.org/10.1155/2022/4111710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8923780PMC
March 2022

Longitudinal Model-Based Meta-Analysis of Lung Function Response to Support Phase III Study Design in Chinese Patients With Asthma.

Clin Pharmacol Ther 2022 06 7;111(6):1286-1295. Epub 2022 Apr 7.

Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, Stevenage, UK.

Asthma is a chronic disease of the lungs characterized by airway inflammation, bronchoconstriction, and increased airway responsiveness. Forced expiratory volume in the first second (FEV1) is used as a measure of lung function and to help diagnose and monitor lung diseases, including asthma. An exponential longitudinal model has been previously developed to adequately describe the FEV1 response in asthma patients with placebo. This model was the basis of a longitudinal model-based meta-analysis which was undertaken to describe the trough FEV1 responses ranging up to 1 year from nine clinical studies in a population with asthma (N = 3,896), following placebo, dual combination (fluticasone furoate/vilanterol), and triple combination (fluticasone furoate/umeclidinium/vilanterol) given via inhalation. Numerical, graphical and simulation-based diagnostics showed that a Weibull model adequately characterized the longitudinal trough FEV1 response with time. Automatic covariate selection supported by statistically based regression models identified a range of patient characteristics influencing the model parameters. Race was a significant covariate on baseline but not on the parameters that impact the FEV1 trajectory. Based on the trough FEV1, all active treatments were found to be significantly different when compared with placebo and showed clinically meaningful improvement in FEV1. The model was able to predict the longitudinal FEV1 response in Chinese patients with inadequately controlled asthma and was used to provide additional support with respect to the design for a shorter-duration phase III study to the China National Medical Products Administration (NMPA).
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http://dx.doi.org/10.1002/cpt.2578DOI Listing
June 2022

Improved Confidence in a Confirmatory Stage by Application of Item-Based Pharmacometrics Model: Illustration with a Phase III Active Comparator-Controlled Trial in COPD Patients.

Pharm Res 2022 Aug 1;39(8):1779-1787. Epub 2022 Mar 1.

Department of Pharmacy, Uppsala University, BMC, Box 580, 751 23, Uppsala, Sweden.

Purpose: The current study aimed to illustrate how a non-linear mixed effect (NLME) model-based analysis may improve confidence in a Phase III trial through more precise estimates of the drug effect.

Methods: The FULFIL clinical trial was a Phase III study that compared 24 weeks of once daily inhaled triple therapy with twice daily inhaled dual therapy in patients with chronic obstructive pulmonary disease (COPD). Patient reported outcome data, obtained by using The Evaluating Respiratory Symptoms in COPD (E-RS:COPD) questionnaire, from the FULFIL study were analyzed using an NLME item-based response theory model (IRT). The change from baseline (CFB) in E-RS:COPD total score over 4-week intervals for each treatment arm was obtained using the IRT and compared with published results obtained with a mixed model repeated measures (MMRM) analysis.

Results: The IRT included a graded response model characterizing item parameters and a Weibull function combined with an offset function to describe the COPD symptoms-time course in patients receiving either triple therapy (n = 907) or dual therapy (n = 894). The IRT improved precision of the estimated drug effect compared to MMRM, resulting in a sample size of at least 3.64 times larger for the MMRM analysis to achieve the IRT precision in the CFB estimate.

Conclusion: This study shows the advantage of IRT over MMRM with a direct comparison of the same primary endpoint for the two analyses using the same observed clinical trial data, resulting in an increased confidence in Phase III.
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http://dx.doi.org/10.1007/s11095-022-03194-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9314306PMC
August 2022

Deubiquitination and Stabilization of PD-L1 by USP21.

Am J Transl Res 2021 15;13(11):12763-12774. Epub 2021 Nov 15.

Department of Biochemistry & Research Center of Clinical Pharmacy of The First Affiliated Hospital, Zhejiang University School of Medicine Hangzhou 310058, Zhejiang, China.

Recent studies have shown that the expression level of PD-L1 in tumor cells positively correlates with tumor metastasis and recurrence rate. The effects of post-translational modifications (PTMs) of PD-L1 are related to immunosuppression. However, the degradation of PD-L1 in cancers has not yet been sufficiently defined. Here, we identified USP21 as a novel deubiquitinase of PD-L1. Overexpression of USP21 significantly increased PD-L1 abundance while its knockdown induced PD-L1 degradation. deubiquitination assay revealed that USP21-WT, but not USP21-C221A, reduced polyubiquitin chains of PD-L1. These results highlight the role of USP21 in the deubiquitination and stabilization of PD-L1. Furthermore, we show that USP21 is the frequently amplified deubiquitinase in lung cancer, especially in lung squamous cell carcinoma, and its amplification is accompanied by upregulation of PD-L1. This study reveals the mechanism of USP21-mediated PD-L1 degradation, and suggests that USP21 might be a potential target for the treatment of lung cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8661224PMC
November 2021

RGS12 inhibits the progression and metastasis of multiple myeloma by driving M1 macrophage polarization and activation in the bone marrow microenvironment.

Cancer Commun (Lond) 2022 01 20;42(1):60-64. Epub 2021 Dec 20.

Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, 19104, United States.

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http://dx.doi.org/10.1002/cac2.12228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8753303PMC
January 2022

Production of Polyhydroxyalkanoates in Unsterilized Hyper-Saline Medium by Halophiles Using Waste Silkworm Excrement as Carbon Source.

Molecules 2021 Nov 25;26(23). Epub 2021 Nov 25.

School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310035, China.

The chlorophyll ethanol-extracted silkworm excrement was hardly biologically reused or fermented by most microorganisms. However, partial extremely environmental halophiles were reported to be able to utilize a variety of inexpensive carbon sources to accumulate polyhydroxyalkanoates. In this study, by using the nile red staining and gas chromatography assays, two endogenous haloarchaea strains: A85 and A112 of silkworm excrement were shown to accumulate poly(3-hydroxybutyrate) up to 0.23 g/L and 0.08 g/L, respectively, when using the silkworm excrement as the sole carbon source. The PHA production of two haloarchaea showed no significant decreases in the silkworm excrement medium without being sterilized compared to that of the sterilized medium. Meanwhile, the CFU experiments revealed that there were more than 60% target PHAs producing haloarchaea cells at the time of the highest PHAs production, and the addition of 0.5% glucose into the open fermentation medium can largely increase both the ratio of target haloarchaea cells (to nearly 100%) and the production of PHAs. In conclusion, our study demonstrated the feasibility of using endogenous haloarchaea to utilize waste silkworm excrement, effectively. The introduce of halophiles could provide a potential way for open fermentation to further lower the cost of the production of PHAs.
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http://dx.doi.org/10.3390/molecules26237122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8659123PMC
November 2021

SAG therapy restores bone growth and reduces enchondroma incidence in a model of skeletal chondrodysplasias caused by Ihh deficiency.

Mol Ther Methods Clin Dev 2021 Dec 1;23:461-475. Epub 2021 Oct 1.

Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Inactivation mutations in the Indian hedgehog (Ihh) gene in humans cause numerous skeletal chondrodysplasias, including acrocapitofemoral dysplasia, brachydactyly type A1, and human short stature. The lack of an appropriate human-relevant model to accurately represent these chondrodysplasias has hampered the identification of clinically effective treatments. Here, we established a mouse model of human skeletal dysplasia induced by Ihh gene mutations via ablation of Ihh in Aggrecan-positive (Acan+) cells using Aggrecan (Acan)-creERT transgenic mice. Smoothen agonist (SAG) promoted Hh activity and rescued chondrocyte proliferation and differentiation by stimulating smoothened trafficking to the cilium in Ihh-silenced cells. SAG treatment corrected mouse stature and significantly decreased mortality without evidence of toxicity. Moreover, Ihh ablation in Acan+ cells produced enchondroma-like tissues near the growth plates that were significantly reduced by SAG treatment. These results demonstrated that SAG effectively treats skeletal dysplasia caused by Ihh gene mutations in a mouse model, suggesting that SAG may represent a potential drug for the treatment of these diseases and/or enchondromas.
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http://dx.doi.org/10.1016/j.omtm.2021.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591400PMC
December 2021

SC75741, A Novel c-Abl Inhibitor, Promotes the Clearance of TDP25 Aggregates ATG5-Dependent Autophagy Pathway.

Front Pharmacol 2021 29;12:741219. Epub 2021 Oct 29.

Department of Biochemistry and Research Center of Clinical Pharmacy of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Abnormal accumulation of TDP43-related mutant proteins in the cytoplasm causes amyotrophic lateral sclerosis (ALS). Herein, unbiased drug screening approaches showed that SC75741, a multi-target inhibitor, inhibited inflammation-induced aggregation by inhibiting NF-κB and also degraded already aggregated proteins by inhibiting c-Abl mediated autophagy-lysosomal pathway. We delineate the mechanism that SC75741 could markedly enhance TFEB nuclear translocation by an mTORC1-independent TFEB regulatory pathway. In addition, SC75741 enhanced the interaction between p62 with TDP25 and LC3C, thus promoting TDP25 degradation. Taken together, these findings show that SC75741 has beneficial neuroprotective effects in ALS. Our study elucidates that dual-targeted inhibition of c-Abl and NF-κB may be a potential treatment for TDP43 proteinopathies and ALS.
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http://dx.doi.org/10.3389/fphar.2021.741219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586708PMC
October 2021

Discovery of davemaoite, CaSiO-perovskite, as a mineral from the lower mantle.

Science 2021 Nov 11;374(6569):891-894. Epub 2021 Nov 11.

Division of Geological and Planetary Sciences, California Institute of Technology, Pasadena, CA 91105, USA.

Calcium silicate perovskite, CaSiO, is arguably the most geochemically important phase in the lower mantle, because it concentrates elements that are incompatible in the upper mantle, including the heat-generating elements thorium and uranium, which have half-lives longer than the geologic history of Earth. We report CaSiO-perovskite as an approved mineral (IMA2020-012a) with the name davemaoite. The natural specimen of davemaoite proves the existence of compositional heterogeneity within the lower mantle. Our observations indicate that davemaoite also hosts potassium in addition to uranium and thorium in its structure. Hence, the regional and global abundances of davemaoite influence the heat budget of the deep mantle, where the mineral is thermodynamically stable.
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http://dx.doi.org/10.1126/science.abl8568DOI Listing
November 2021

The E3 ubiquitin ligase DESYNAPSIS1 regulates synapsis and recombination in rice meiosis.

Cell Rep 2021 11;37(5):109941

State Key Lab of Plant Genomics, Institute of Genetics and Developmental Biology, Innovation Academy for Seed Design, Chinese Academy of Sciences, 100101 Beijing, China; Jiangsu Co-Innovation Center for Modern Production Technology of Grain Crops, Yangzhou University, Yangzhou, 225009, China. Electronic address:

Synaptonemal complex (SC) assembly and homologous recombination, the most critical events during prophase I, are the prerequisite for faithful meiotic chromosome segregation. However, the underlying regulatory mechanism remains largely unknown. Here, we reveal that a functional RING finger E3 ubiquitin ligase, DESYNAPSIS1 (DSNP1), plays significant roles in SC assembly and homologous recombination during rice meiosis. In the dsnp1 mutant, homologous synapsis is discontinuous and aberrant SC-like polycomplexes occur independent of coaligned homologous chromosomes. Accompanying the decreased foci of HEI10, ZIP4, and MER3 on meiotic chromosomes, the number of crossovers (COs) decreases dramatically in dsnp1 meiocytes. Furthermore, the absence of central elements largely restores the localization of non-ZEP1 ZMM proteins and the number of COs in the dsnp1 background. Collectively, DSNP1 stabilizes the canonical tripartite SC structure along paired homologous chromosomes and further promotes the formation of COs.
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http://dx.doi.org/10.1016/j.celrep.2021.109941DOI Listing
November 2021

Diabetes impairs fracture healing through disruption of cilia formation in osteoblasts.

Bone 2021 12 9;153:116176. Epub 2021 Sep 9.

Department of Basic and Translation Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Innovation & Precision Dentistry, School of Dental Medicine, School of Engineering and Applied Sciences, University of Pennsylvania, PA 19104, USA; The Penn Center for Musculoskeletal Disorders, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Diabetes-associated fracture risk and impaired fracture healing represents a serious health threat. It is well known that type 1 diabetes mellitus (T1DM) impairs fracture healing due to its effect on osteoblasts and their progenitor cells. Previous studies have showed that primary cilia and intraflagellar transport protein 80 (IFT80) are critical for bone formation. However, whether TIDM impairs fracture healing due to influencing ciliary gene expression and cilia formation is unknown. Here, we investigated the effect of T1DM on primary cilia in a streptozotocin induced diabetes mouse model and examined the impact of cilia on fracture healing in osteoblasts by deletion of IFT80 in osteoblast linage using osterix (OSX)-cre (OSXIFT80). The results showed that diabetes inhibited ciliary gene expression and primary cilia formation to an extent that was similar to normoglycemic mice with IFT80 deletion. Moreover, diabetic mice and normoglycemic mice with cilia loss in osteoblasts (OSXIFT80) both exhibited delayed fracture healing with significantly reduced bone density and mechanical strength as well as with reduced expression of osteoblast markers, decreased angiogenesis and proliferation of bone lining cells at the fracture sites. In vitro studies showed that advanced glycation end products (AGEs) downregulated IFT80 expression in osteoblast progenitors. Moreover, AGEs and IFT80 deletion significantly reduced cilia number and length which inhibited differentiation of primary osteoblast precursors. Thus, this study for the first time report that primary cilia are essential for bone regeneration during fracture healing and loss of cilia caused by diabetes in osteoblasts resulted in defective diabetic fracture healing.
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http://dx.doi.org/10.1016/j.bone.2021.116176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9160738PMC
December 2021

Control of Cell Geometry through Infrared Laser Assisted Micropatterning.

J Vis Exp 2021 07 10(173). Epub 2021 Jul 10.

Department of Cell and Systems Biology, University of Toronto;

Micropatterning is an established technique in the cell biology community used to study connections between the morphology and function of cellular compartments while circumventing complications arising from natural cell-to-cell variations. To standardize cell shape, cells are either confined in 3D molds or controlled for adhesive geometry through adhesive islands. However, traditional micropatterning techniques based on photolithography and deep UV etching heavily depend on clean rooms or specialized equipment. Here we present an infrared laser assisted micropatterning technique (microphotopatterning) modified from Doyle et al. that can be conveniently set up with commercially available imaging systems. In this protocol, we use a Nikon A1R MP+ imaging system to generate micropatterns with micron precision through an infrared (IR) laser that ablates preset regions on poly-vinyl alcohol coated coverslips. We employ a custom script to enable automated pattern fabrication with high efficiency and accuracy in systems not equipped with a hardware autofocus. We show that this IR laser assisted micropatterning (microphotopatterning) protocol results in defined patterns to which cells attach exclusively and take on the desired shape. Furthermore, data from a large number of cells can be averaged due to the standardization of cell shape. Patterns generated with this protocol, combined with high resolution imaging and quantitative analysis, can be used for relatively high throughput screens to identify molecular players mediating the link between form and function.
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http://dx.doi.org/10.3791/62492DOI Listing
July 2021

Evaluation of area under the concentration curve adjusted by the terminal-phase as a metric to reduce the impact of variability in bioequivalence testing.

Br J Clin Pharmacol 2022 02 24;88(2):619-627. Epub 2021 Aug 24.

Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Brentford, Middlesex, UK.

Aim: To quantify the utility of a terminal-phase adjusted area under the concentration curve method in increasing the probability of a correct and conclusive outcome of a bioequivalence (BE) trial for highly variable drugs when clearance (CL) varies more than the volume of distribution (V).

Methods: Data from a large population of subjects were generated with variability in CL and V, and used to simulate a two-period, two-sequence crossover BE trial. The 90% confidence interval for formulation comparison was determined following BE assessment using the area under the concentration curve (AUC) ratio test, and the proposed terminal-phase adjusted AUC ratio test. An outcome of bioequivalent, nonbioequivalent or inconclusive was then assigned according to predefined BE limits.

Results: When CL varied more than V, the proposed approach enhanced the probability of correctly assigning bioequivalent or nonbioequivalent and reduced the risk of an inconclusive trial. For a hypothetical drug with between-subject variability of 35% for CL and 10% for V, when the true test-reference ratio of bioavailability was 1.15, a crossover study of n = 14 subjects analysed by the proposed method would have 80% or 20% probability of claiming bioequivalent or nonbioequivalent, compared to 22%, 46% or 32% probability of claiming bioequivalent, nonbioequivalent or inconclusive using the standard AUC ratio test.

Conclusions: The terminal-phase adjusted AUC ratio test represents a simple and readily applicable approach to enhance the BE assessment of drug products when CL varies more than V.
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http://dx.doi.org/10.1111/bcp.14986DOI Listing
February 2022

Identification of Cilia in Different Mouse Tissues.

Cells 2021 06 29;10(7). Epub 2021 Jun 29.

Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Cilia are microtubule-based hair-like organelles that extend from the cell surface. However, the existence and distribution of cilia in each organ and tissue at the postnatal stage in vivo remain largely unknown. In this study, we defined cilia distribution and arrangement and measured the ciliary lengths and the percentage of ciliated cells in different organs and tissues in vivo by using cilium dual reporter-expressing transgenic mice. Cilia were identified by the presence of ARL13B with an mCherry+ signal, and the cilium basal body was identified by the presence of Centrin2 with a GFP+ signal. Here, we provide in vivo evidence that chondrocytes and cells throughout bones have cilia. Most importantly, we reveal that: 1. primary cilia are present in hepatocytes; 2. no cilia but many centrioles are distributed on the apical cell surface in the gallbladder, intestine, and thyroid epithelia; 3. cilia on the cerebral cortex are well oriented, pointing to the center of the brain; 4. ARL13B+ inclusion is evident in the thyroid and islets of Langerhans; and 5. approximately 2% of cilia show irregular movement in nucleus pulposus extracellular fluid. This study reveals the existence and distribution of cilia and centrioles in different tissues and organs, and provides new insights for further comprehensive study of ciliary function in these organs and tissues.
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http://dx.doi.org/10.3390/cells10071623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307782PMC
June 2021

Improved Decision-Making Confidence Using Item-Based Pharmacometric Model: Illustration with a Phase II Placebo-Controlled Trial.

AAPS J 2021 06 2;23(4):79. Epub 2021 Jun 2.

Department of Pharmacy, Uppsala University, Box 580, 751 23, Uppsala, Sweden.

This study aimed to illustrate how a new methodology to assess clinical trial outcome measures using a longitudinal item response theory-based model (IRM) could serve as an alternative to mixed model repeated measures (MMRM). Data from the EXACT (Exacerbation of chronic pulmonary disease tool) which is used to capture frequency, severity, and duration of exacerbations in COPD were analyzed using an IRM. The IRM included a graded response model characterizing item parameters and functions describing symptom-time course. Total scores were simulated (month 12) using uncertainty in parameter estimates. The 50th (2.5th, 97.5th) percentiles of the resulting simulated differences in average total score (drug minus placebo) represented the estimated drug effect (95%CI), which was compared with published MMRM results. Furthermore, differences in sample size, sensitivity, specificity, and type I and II errors between approaches were explored. Patients received either oral danirixin 75 mg twice daily (n = 45) or placebo (n = 48) on top of standard of care over 52 weeks. A step function best described the COPD symptoms-time course in both trial arms. The IRM improved precision of the estimated drug effect compared to MMRM, resulting in a sample size of 2.5 times larger for the MMRM analysis to achieve the IRM precision. The IRM showed a higher probability of a positive predictive value (34%) than MMRM (22%). An item model-based analysis data gave more precise estimates of drug effect than MMRM analysis for the same endpoint in this one case study.
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http://dx.doi.org/10.1208/s12248-021-00600-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172506PMC
June 2021

Type II collagen-positive embryonic progenitors are the major contributors to spine and intervertebral disc development and repair.

Stem Cells Transl Med 2021 10 25;10(10):1419-1432. Epub 2021 May 25.

Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Basic mechanism of spine development is poorly understood. Type II collagen positive (Col2+) cells have been reported to encompass early mesenchymal progenitors that continue to become chondrocytes, osteoblasts, stromal cells, and adipocytes in long bone. However, the function of Col2+ cells in spine and intervertebral disc (IVD) development is largely unknown. To further elucidate the function of Col2+ progenitors in spine, we generated the mice with ablation of Col2+ cells either at embryonic or at postnatal stage. Embryonic ablation of Col2+ progenitors caused the mouse die at newborn with the absence of all spine and IVD. Moreover, postnatal deletion Col2+ cells in spine resulted in a shorter growth plate and endplate cartilage, defected inner annulus fibrosus, a less compact and markedly decreased gel-like matrix in the nucleus pulposus and disorganized cell alignment in each compartment of IVD. Genetic lineage tracing IVD cell populations by using inducible Col2-creERT;tdTomato reporter mice and non-inducible Col2-cre;tdTomato reporter mice revealed that the numbers and differentiation ability of Col2+ progenitors decreased with age. Moreover, immunofluorescence staining showed type II collagen expression changed from extracellular matrix to cytoplasm in nucleus pulposus between 6 month and 1-year-old mice. Finally, fate-mapping studies revealed that Col2+ progenitors are essential for IVD repair in IVD injured model. In summary, embryonic Col2+ cells are the major source of spine development and Col2+ progenitors are the important contributors for IVD repair and regeneration.
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http://dx.doi.org/10.1002/sctm.20-0424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459639PMC
October 2021

Quantitative Analysis of Myofibroblast Contraction by Traction Force Microscopy.

Methods Mol Biol 2021 ;2299:181-195

Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada.

Myofibroblasts play important roles in physiological processes such as wound healing and tissue repair. While high contractile forces generated by the actomyosin network enable myofibroblasts to physically contract the wound and bring together injured tissue, prolonged and elevated levels of contraction also drive the progression of fibrosis and cancer. However, quantitative mapping of these forces has been difficult due to their extremely low magnitude ranging from 100 pN/μm to 2 nN/μm. Here, we provide a protocol to measure cellular forces exerted on two-dimensional compliant elastic hydrogels. We describe the fabrication of polyacrylamide hydrogels labeled with fluorescent fiducial markers, functionalization of substrates with ECM proteins, setting up the experiment, and imaging procedures. We demonstrate the application of this technique for quantitative analysis of traction forces exerted by myofibroblasts.
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http://dx.doi.org/10.1007/978-1-0716-1382-5_14DOI Listing
August 2021

Detecting placebo and drug effects on Parkinson's disease symptoms by longitudinal item-score models.

CPT Pharmacometrics Syst Pharmacol 2021 04;10(4):309-317

Department of Pharmacy, Uppsala University, Uppsala, Sweden.

This study tested the hypothesis that analyzing longitudinal item scores of the Unified Parkinson's Disease Rating Scale could allow a smaller trial size and describe a drug's effect on symptom progression. Two historical studies of the dopaminergic drug ropinirole were analyzed: a cross-over formulation comparison trial in 161 patients with early-stage Parkinson's disease, and a 24-week, parallel-group, placebo-controlled efficacy trial in 393 patients with advanced-stage Parkinson's disease. We applied item response theory to estimate the patients' symptom severity and developed a longitudinal model using the symptom severity to describe the time course of the placebo response and the drug effect on the time course. Similarly, we developed a longitudinal model using the total score. We then compared sample size needs for drug effect detection using these two different models. Total score modeling estimated median changes from baseline at 24 weeks (90% confidence interval) of -3.7 (-5.4 to -2.0) and -9.3 (-11 to -7.3) points by placebo and ropinirole. Comparable changes were estimated (with slightly higher precision) by item-score modeling as -2.0 (-4.0 to -1.0) and -9.0 (-11 to -8.0) points. The treatment duration was insufficient to estimate the symptom progression rate; hence the drug effect on the progression could not be assessed. The trial sizes to detect a drug effect with 80% power on total score and on symptom severity were estimated (at the type I error level of 0.05) as 88 and 58, respectively. Longitudinal item response analysis could markedly reduce sample size; it also has the potential for assessing drug effects on disease progression in longer trials.
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http://dx.doi.org/10.1002/psp4.12601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099436PMC
April 2021

Mechanosensitive Regulation of Fibrosis.

Cells 2021 04 23;10(5). Epub 2021 Apr 23.

Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada.

Cells in the human body experience and integrate a wide variety of environmental cues. A growing interest in tissue mechanics in the past four decades has shown that the mechanical properties of tissue drive key biological processes and facilitate disease development. However, tissue stiffness is not only a potent behavioral cue, but also a product of cellular signaling activity. This review explores both roles of tissue stiffness in the context of inflammation and fibrosis, and the important molecular players driving such processes. During inflammation, proinflammatory cytokines upregulate tissue stiffness by increasing hydrostatic pressure, ECM deposition, and ECM remodeling. As the ECM stiffens, cells involved in the immune response employ intricate molecular sensors to probe and alter their mechanical environment, thereby facilitating immune cell recruitment and potentiating the fibrotic phenotype. This powerful feedforward loop raises numerous possibilities for drug development and warrants further investigation into the mechanisms specific to different fibrotic diseases.
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http://dx.doi.org/10.3390/cells10050994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145148PMC
April 2021

TAZ is required for chondrogenesis and skeletal development.

Cell Discov 2021 Apr 20;7(1):26. Epub 2021 Apr 20.

Department of Basic & Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Chondrogenesis is a major contributor to skeletal development and maintenance, as well as bone repair. Transcriptional coactivator with PDZ-binding motif (TAZ) is a key regulator of osteogenesis and adipogenesis, but how TAZ regulates chondrogenesis and skeletal development remains undefined. Here, we found that TAZ expression is gradually increased during chondrogenic differentiation. Deletion of TAZ in chondrocyte lineage impaired articular and growth plate, as well as the bone development in TAZ-deficient mice. Consistently, loss of TAZ impaired fracture healing. Mechanistically, we found that ectopic expression of TAZ markedly promoted chondroprogenitor proliferation, while deletion of TAZ impaired chondrocyte proliferation and differentiation. TAZ associated with Sox5 to regulate the expression and stability of Sox5 and downstream chondrocyte marker genes' expression. In addition, overexpression of TAZ enhanced Col10a1 expression and promoted chondrocyte maturation, which was blocked by deletion of TAZ. Overall, our findings demonstrated that TAZ is required for skeletal development and joint maintenance that provided new insights into therapeutic strategies for fracture healing, heterotopic ossification, osteoarthritis, and other bone diseases.
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http://dx.doi.org/10.1038/s41421-021-00254-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058044PMC
April 2021
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