Kdm6b regulates cartilage development and homeostasis through anabolic metabolism

Dai, Jun; Yu, Dongsheng; Wang, Yafei; Chen, Yishan; Sun, Heng; Zhang, Xiaolei; Zhu, Shouan; Pan, Zongyou; Heng, Boon Chin; Zhang, Shufang; Ouyang, Hongwei

doi:10.1136/annrheumdis-2016-210407

Cited by 53 publications

(46 citation statements)

References 39 publications

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“…We have previously studied its expression in OA cartilage samples, and its deletion effects on OA progression. In contrast to EZH2, we revealed that the number of KDM6B‐positive chondrocytes was lower in both mice and human OA cartilage samples . With the same system of conditional knockout mice ( Col2a1‐CreER T2 ), we demonstrated that the chondrocyte‐specific deletion of KDM6B would decrease the expression of chondrocyte anabolic genes, and remarkably, would also deteriorate surgical‐induced OA development.…”

Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

“…It was recently revealed that epigenetic regulation is involved in OA pathology and skeletal growth disorders . Our group recently found that the H3K27 (lysine 27 on histone H3) demethylase KDM6B regulated chondrocyte anabolic metabolism in vivo . Interestingly, the expression of Enhancer of Zeste Homolog 2 (EZH2), which catalyzes the trimethylation of H3K27, is elevated during the pathological process of OA in vitro .…”

Section: Introductionmentioning

confidence: 99%

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Ezh2 Ameliorates Osteoarthritis by Activating TNFSF13B

Chen

Zhang

et al. 2020

Journal of Bone and Mineral Research

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Epigenetic regulation is highly correlated with osteoarthritis (OA) development, whereas its role and detailed mechanisms remain elusive. In this study, we explored the expression of EZH2, an H3K27me3 transferase, in human OA cartilages and its roles in regulating OA pathogenesis. Here, we found EZH2 was highly expressed in both mice and human OA cartilage samples by using histological analysis and RNA sequencing (RNA-Seq). The medial meniscectomy (MMx) OA model results indicated the conditional knockout of Ezh2 deteriorated OA pathological conditions. Furthermore, we showed the positive role of Ezh2 in cartilage wound healing and inhibition of hypertrophy through activating TNFSF13B, a member of the tumor necrosis factor superfamily. Further, we also indicated that the effect of TNFSF13B, increased by Ezh2, might boost the healing of chondrocytes through increasing the phosphorylation of Akt. Taken together, our results uncovered an EZH2-positive subpopulation existed in OA patients, and that EZH2-TNFSF13B signaling was responsible for regulating chondrocyte healing and hypertrophy. Thus, EZH2 might act as a new potential target for OA diagnosis and treatment. n 956 DU ET AL. 23. Ohata J, Zvaifler NJ, Nishio M, et al. Fibroblast-like synoviocytes of mesenchymal origin express functional B cell-activating factor of the TNF family in response to proinflammatory cytokines. J Immunol. 2005;174(2):864-70. 24. Bradley EW, Carpio LR, Westendorf JJ. Histone deacetylase 3 suppression increases PH domain and leucine-rich repeat phosphatase (Phlpp)1 expression in chondrocytes to suppress Akt signaling and matrix secretion. J Biol Chem. 2013;288:9572-82. 25. Zhang S, Chuah SJ, Lai RC, JHP H, Lim SK, Toh WS. MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials. 2018;156: 16-27. Journal of Bone and Mineral Research n 964 DU ET AL.

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ezh2 Ameliorates Osteoarthritis by Activating TNFSF13B

Chen

Zhang

et al. 2020

Journal of Bone and Mineral Research

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“…2017KYLL11). Detailed human cartilage information was described in our previous study 25 . The human cartilage was utilized for subsequent isolation of primary chondrocytes immediately after collection.…”

Section: Primary Chondrocytesmentioning

confidence: 99%

“…Immunostaining was performed using a standard protocol as previously described 25 . Primary antibodies were: anti-MINK1 (NO.NBP1-22990, Novus Biologicals), anti-COL2A1 (NO.sc-52658, Santa Cruz Biotechnology Inc.), anti-Aggrecan Neoepitope (NO.NBP100-74350, Novus Biologicals), anti-pSMAD2 (NO.3108, Cell Signaling Technology), anti-osterix (NO.ab22552, Abcam), antiosteocalcin (NO.AB10911, Millipore), anti-VEGF (NO.ab46154, Abcam), anti-MMP13 (NO.…”

Section: Embryo Limbsmentioning

confidence: 99%

Dual roles of misshapen/NIK-related kinase (MINK1) in osteoarthritis subtypes through the activation of TGFβ signaling

Sheng

et al. 2020

Osteoarthritis and Cartilage

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Objective: To identify the role of misshapen/NIK-related kinase (MINK1) in age-related Osteoarthritis (OA) and injury-induced OA, and the effects of enhanced TGFb signaling in these progresses. Design: The effect of MINK1 was analyzed with MINK1 knock out (Mink1À/À) mice and C57BL/6J mice. OA progress was studied in age-related OA and instability-associated OA (destabilization of the medial meniscus, DMM) models. The murine knee joint was evaluated through histological staining, Osteoarthritis Research Society International (OARSI) scores, immunohistochemistry, and mCT analysis. Primary chondrocytes were isolated from wild type and Mink1À/À mice and subjected to osteogenic induction and Western blot analysis. Results: MINK1 is highly expressed during cartilage development and in normal cartilage. Mink1À/À mice displayed markedly lower OARSI scores, aggrecan degradation neoepitope positive cells and increased Safranin O and pSMAD2 staining in aging-related OA model. However, in injury-induced OA, loss of MINK1 accelerates extracellular matrix (ECM) destruction, osteophyte formation, and subchondral bone sclerosis. Accelerated subchondral bone remodeling in Mink1À/À mice was accompanied with increased numbers of nestin-positive mesenchymal stem cells (MSCs) and osterix-positive osteoprogenitors. pSMAD2 staining was increased in the subchondral bone marrow of Mink1À/À mice and overexpression of MINK1 inhibited SMAD2 phosphorylation in vitro. Conclusions: This study shows for the first time that activation of TGFb/SMAD2 by MINK1 deficiency plays opposite roles in aging-related and injury-induced OA. MINK1 deficiency protects cartilage from degeneration in aging joints through increased SMAD2 activation in chondrocytes, while accelerating OA progress in injury-induced model through enhanced osteogenesis of MSCs in the subchondral bone. These findings provide insights for developing precision OA therapeutics targeting TGFb/SMAD2 signaling.

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Stem Cell‐Recruiting Injectable Microgels for Repairing Osteoarthritis

Lei

Wang

Shen

et al. 2021

Adv Funct Materials

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The differentiation potentials and viability of stem cells are often impaired during cell isolation and delivery. Inspired by the phenomenon where islands can recruit seabirds for nesting, "cell island" microgels (MGs), that is, growth factor-loaded methacrylated hyaluronic acid and heparin blend MGs, which can recruit endogenous stem cells and promote chondrogenic differentiation, are constructed using microfluidic technology and photopolymerization processes, followed by non-covalently binding platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-beta3 (TGF-β3). The loading efficiency of PDGF-BB and TGF-β3 are 96% and 91%, respectively. In vitro and in vivo experiments find that the "cell island" MGs can enhance the migratory capacity of cells and recruit them from their niche via releasing PDGF-BB. Meanwhile, by using hyaluronic acid, the "cell island" MGs provide a suitable microenvironment for cell attachment and spreading. Furthermore, the "cell island" MGs induce chondrogenic differentiation of the recruited cells via releasing TGF-β3 and present a promising therapeutic effect for osteoarthritis. In sum, this developed "cell island" MG might serve as a temporary "nest site" to allow the migration, adhesion, and differentiation of endogenous stem cells, which can be a promising candidate rather than the conventional cell-seeded scaffolds for promoting tissue regeneration.

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Kdm6b regulates cartilage development and homeostasis through anabolic metabolism

Cited by 53 publications

References 39 publications

Ezh2 Ameliorates Osteoarthritis by Activating TNFSF13B

Ezh2 Ameliorates Osteoarthritis by Activating TNFSF13B

Dual roles of misshapen/NIK-related kinase (MINK1) in osteoarthritis subtypes through the activation of TGFβ signaling

Stem Cell‐Recruiting Injectable Microgels for Repairing Osteoarthritis

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