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

ABSTRACT: 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 Col10a1-Sox9 transgenic mouse model, in which Sox9 is specifically expressed in hypertrophic chondrocytes driven by a well-characterized 10-kb Col10a1 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 Col10a1, 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 Col10a1-Sox9 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 Sox9 is necessary for normal adult hypertrophic cartilage homeostasis, and that the aberrant expression of Sox9 might lead to spontaneous OA development.

SUBMITTER: Liang B

PROVIDER: S-EPMC7137053 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Liang Bojian B Mamidi Murali K MK Samsa William E WE Chen Yuqing Y Lee Brendan B Zheng Qiping Q Zhou Guang G

American journal of translational research 20200315 3

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 Col10a1-Sox9 transgenic mouse model, in which Sox9 is specifically expressed in hypertrophic chondrocytes driven by a well-characterized 10-kb Col10a1 promoter. These mice were viable and fertile, and appeared normal at birth. However, they developed dwarfism by ten weeks of age. The histolo ...[more]

PMID: 32269734

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Project description:We previously found that FoxA factors are necessary for chondrocyte differentiation. To investigate whether FoxA factors alone are sufficient to drive chondrocyte hypertrophy, we build a FoxA2 transgenic mouse in which FoxA2 cDNA is driven by a reiterated Tetracycline Response Element (TRE) and a minimal CMV promoter. This transgenic line was crossed with a col2CRE;Rosa26rtTA/+ mouse line to generate col2CRE;Rosa26rtTA/+;TgFoxA2+/- mice for inducible expression of FoxA2 in cartilage using doxycycline treatment. Ectopic expression of FoxA2 in the developing skeleton reveals skeletal defects and shorter skeletal elements in E17.5 mice. The chondro-osseous border was frequently mis-shaped in mutant mice, with small islands of col.10+ hypertrophic cells extending in the metaphyseal bone. Even though overexpression of FoxA2 causes an accumulation of hypertrophic chondrocytes, it did not trigger ectopic hypertrophy in the immature chondrocytes. This suggests that FoxA2 may need transcriptional co-factors (such as Runx2), whose expression is restricted to the hypertrophic zone, and absent in the immature chondrocytes. To investigate a potential FoxA2/Runx2 interaction in immature chondrocytes versus hypertrophic cells, we separated these two subpopulations by FACS to obtain CD24+CD200+ hypertrophic chondrocytes and CD24+CD200- immature chondrocytes and we ectopically expressed FoxA2 alone or in combination with Runx2 via lentiviral gene delivery. In CD24+CD200+ hypertrophic chondrocytes, FoxA2 enhanced the expression of chondrocyte hypertrophic markers collagen 10, MMP13, and alkaline phosphatase. In contrast, in the CD24+CD200- immature chondrocytes, neither FoxA2 nor Runx2 overexpression could induce ectopic expression of hypertrophic markers MMP13, alkaline phosphatase, or PTH/PTHrP receptor. Overall these findings mirror our in vivo data, and suggest that induction of chondrocyte hypertrophy by FoxA2 may require other factors in addition to Runx2 (i.e., Hif2α, MEF2C, or perhaps unknown factors), whose expression/activity is rate-limiting in immature chondrocytes.

Dataset Information

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

Publications

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

Similar Datasets

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