Targeted and sustained Sox9 expression in mouse hypertrophic chondrocytes causes severe and spontaneous osteoarthritis by perturbing cartilage homeostasis.

Sox9 is the master transcription factor essential for cartilage development and homeostasis. To investigate the specific role of Sox9 during chondrocyte hypertrophy, we generated a novel transgenic mouse model, in which is specifically expressed in hypertrophic chondrocytes driven by a well-characterized 10-kb promoter. These mice were viable and fertile, and appeared normal at birth. However, they developed dwarfism by ten weeks of age. The histological analysis of the growth plates from these transgenic mice demonstrated an abnormal growth plate architecture and a significantly reduced amount of trabecular bone and mineral content in the primary spongiosa. Real-time qPCR analysis revealed the reduced expression of , and increased expressions of adipogenic differentiation markers in primary hypertrophic chondrocytes isolated from transgenic mice. Concomitantly, the transgenic mouse chondrocyte cultures had increased lipid droplet accumulation. Unexpectedly, we also observed an increased incidence of spontaneous osteoarthritis (OA) development in the transgenic mice by X-ray analysis, micro-computed tomography scanning, and histological examination of knee joints. The manifestation of OA in transgenic mice began by six-months of age, and worsened by eleven-months of age. In conclusion, we provide strong evidence that the proper spatiotemporal expression of is necessary for normal adult hypertrophic cartilage homeostasis, and that the aberrant expression of might lead to spontaneous OA development.