Objective: Chondrocyte hypertrophic differentiation, a key process in endochondral ossification, is also a feature of osteoarthritis leading to cartilage destruction. Here we investigated the role of the adaptor protein Src homology and Collagen A (ShcA) in chondrocyte differentiation and osteoarthritis.
Methods: Mice ablated for ShcA in osteochondroprogenitor cells were generated by crossing mice carrying the Twist2-Cre transgene with ShcAflox/flox mice. Their phenotype (n = 5 to 14 mice per group) was characterized using histology, immuno-histology and western-blot. To identify the signaling mechanisms involved, in vitro experiments were conducted on wild type and ShcA deficient chondrocytes (isolated from n = 4 to 7 littermates) and the chondroprogenitor cell line ATDC5 (n = 4 independent experiments) using western-blot, cell fractionation and confocal microscopy.
Results: Deletion of ShcA decreases the hypertrophic zone of the growth plate (median between group difference -11.37% [95% confidence interval -17.34 to -8.654]), alters the endochondral ossification process, and leads to dwarfism (3 months old male mice nose-to-anus length -1.48 cm [-1.860 to -1.190]). ShcA promotes ERK1/2 activation, nuclear translocation of RunX2, the master transcription factor for chondrocyte hypertrophy, while maintaining the Runx2 inhibitor, YAP1, in its cytosolic inactive form. This leads to hypertrophic commitment and expression of markers of hypertrophy, such as Collagen X. In addition, loss of ShcA protects from age-related osteoarthritis development in mice (2 years old mice OARSI score -6.67 [-14.25 to -4.000]).
Conclusion: This study reveals ShcA as a new player in the control of chondrocyte hypertrophic differentiation and its deletion slows down osteoarthritis development.
Keywords: Chondrocyte hypertrophy; Endochondral ossification; Osteoarthritis; ShcA.
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