PMID:29503843

Citation	Zhao, C, Jiang, W, Zhou, N, Liao, J, Yang, M, Hu, N, Liang, X, Xu, W, Chen, H, Liu, W, Shi, LL, Oliveira, L, Wolf, JM, Ho, S, Athiviraham, A, Tsai, HM, He, TC and Huang, W (2017) Sox9 augments BMP2-induced chondrogenic differentiation by downregulating Smad7 in mesenchymal stem cells (MSCs). Genes Dis 4:229-239
Abstract	Cartilage injuries caused by arthritis or trauma pose formidable challenges for effective clinical management due to the limited intrinsic proliferative capability of chondrocytes. Autologous stem cell-based therapies and transgene-enhanced cartilage tissue engineering may open new avenues for the treatment of cartilage injuries. Bone morphogenetic protein 2 (BMP2) induces effective chondrogenesis of mesenchymal stem cells (MSCs) and can thus be explored as a potential therapeutic agent for cartilage defect repair. However, BMP2 also induces robust endochondral ossification. Although the precise mechanisms through which BMP2 governs the divergence of chondrogenesis and osteogenesis remain to be fully understood, blocking endochondral ossification during BMP2-induced cartilage formation may have practical significance for cartilage tissue engineering. Here, we investigate the role of Sox9-donwregulated Smad7 in BMP2-induced chondrogenic differentiation of MSCs. We find that overexpression of Sox9 leads to a decrease in BMP2-induced Smad7 expression in MSCs. Sox9 inhibits BMP2-induced expression of osteopontin while enhancing the expression of chondrogenic marker Col2a1 in MSCs. Forced expression of Sox9 in MSCs promotes BMP2-induced chondrogenesis and suppresses BMP2-induced endochondral ossification. Constitutive Smad7 expression inhibits BMP2-induced chondrogenesis in stem cell implantation assay. Mouse limb explant assay reveals that Sox9 expands BMP2-stimulated chondrocyte proliferating zone while Smad7 promotes BMP2-intitated hypertrophic zone of the growth plate. Cell cycle analysis indicates that Smad7 induces significant early apoptosis in BMP2-stimulated MSCs. Taken together, our results strongly suggest that Sox9 may facilitate BMP2-induced chondrogenesis by downregulating Smad7, which can be exploited for effective cartilage tissue engineering.
Links	PubMed PMC5831333 Online version:10.1016/j.gendis.2017.10.004
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:SOX9		GO:0000122: negative regulation of transcription by RNA polymerase II	ECO:0000314:		P		Fig 2A and 2B, Sox9 down-regulates BMP2-induced expression of Smad7. Organism: Human	complete CACAO 13152
HUMAN:SOX9		GO:0030279: negative regulation of ossification	ECO:0000314:		P		Fig; 4 A-c shows that mineral is significantly decreased with BMP2 and Sox9 compared to the control of just BMP2. Organism: Human	complete CACAO 13212
HUMAN:SOX9		GO:0061036: positive regulation of cartilage development	ECO:0000314:		P		“Alcian blue staining analysis indicates that Sox9 significantly promoted BMP2-induced cartilage formation from MSCs (Figure 4C-c)” Organism: Human	complete CACAO 13281
HUMAN:SOX9		GO:1902732: positive regulation of chondrocyte proliferation	ECO:0000314:		P		At the endpoint we analyzed the cultured explants histologically and found that BMP2 promoted a coordinated expansion of cartilage zones at the growth plat, while Sox9 overexpression enhanced BMP2-induced expansion of proliferating chondrocyte zone (Figure 5Bb)” Organism: Human	complete CACAO 13283
MOUSE:SMAD7		GO:0030279: negative regulation of ossification	ECO:0000314:		P		Fig;4 A-c shows that mineral is significantly decreased with BMP2 and SMAD7 compared to the control of just BMP2. Organism: Mouse	complete CACAO 13213
MOUSE:SMAD7		GO:1903043: positive regulation of chondrocyte hypertrophy	ECO:0000314:		P		“overexpression of Smad7 led to a significant expansion of the hypertrophic chondrocyte zone,” compared to just BMP2 Figure 5AB Organism: Mouse	complete CACAO 13206
MOUSE:SMAD7		GO:1902731: negative regulation of chondrocyte proliferation	ECO:0000314:		P		“overexpression of Smad7 led to decreasing the proliferating chondrocyte zone” compared to just BMP2 (Figure 5Bb) Organism: Mouse	complete CACAO 13208

References

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