Transforming Growth Factor-β-Induced KDM4B Promotes Chondrogenic Differentiation of Human Mesenchymal Stem Cells.
The high prevalence of cartilage diseases and limited treatment options create a significant biomedical burden. Due to the inability of cartilage to regenerate itself, introducing chondrocyte progenitor cells to the affected site is of significant interest in cartilage regenerative therapies. Tissue engineering approaches using human mesenchymal stem cells (MSCs) are promising due to their chondrogenic potential, but a comprehensive understanding of the mechanisms governing the fate of MSCs is required for precise therapeutic applications in cartilage regeneration. TGF-β is known to induce chondrogenesis by activating SMAD signaling pathway and upregulating chondrogenic genes such as SOX9; however, the epigenetic regulation of TGF-β-mediated chondrogenesis is not understood. In this report, we found that TGF-β dramatically induced the expression of KDM4B in MSCs. When KDM4B was overexpressed, chondrogenic differentiation was significantly enhanced while KDM4B depletion by shRNA led to a significant reduction in chondrogenic potential. Mechanistically, upon TGF-β stimulation, KDM4B was recruited to the SOX9 promoter, removed the silencing H3K9me3 marks, and activated the transcription of SOX9. Furthermore, KDM4B depletion reduced the occupancy of SMAD3 in the SOX9 promoter, suggesting that KDM4B is required for SMAD-dependent coactivation of SOX9. Our results demonstrate the critical role of KDM4B in the epigenetic regulation of TGF-β-mediated chondrogenic differentiation of MSCs. Since histone demethylases are chemically modifiable, KDM4B may be a novel therapeutic target in cartilage regenerative therapy.
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, California, USA.
Hye-Lim
HL
Lee
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, California, USA.
Bo
B
Yu
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, California, USA.|State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, SiChuan University, Chengdu, Sichuan Province, China.
Peng
P
Deng
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, California, USA.
Cun-Yu
CY
Wang
Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry and Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, California, USA.|Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, California, USA.
Christine
C
Hong
D002356:Cartilage / Q000254:growth & development / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology; D020219:Chondrogenesis / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000096:biosynthesis* / Q000235:genetics; D059630:Mesenchymal Stem Cells; D010012:Osteogenesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D012038:Regeneration; D055758:SOX9 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics*
C497790:SMAD3 protein, human; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D056484:Jumonji Domain-Containing Histone Demethylases; C523637:KDM4B protein, human
Chondrogenesis; Differentiation; KDM4B; Mesenchymal stem cells; SOX9; Transforming growth factor-β