miR-205a mediated suppression of CDH11 disrupts Wnt/β-catenin signaling and impairs chondrocyte differentiation

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Abstract
The precise regulation of chondrocyte differentiation is critical for endochondral ossification, and its disruption underlies a spectrum of skeletal diseases. While the Wnt/β-catenin signaling pathway is a well-established master regulator of skeletal development, its precise regulation during chondrogenesis remains incompletely understood. Here, we identify a novel regulatory axis centered on microRNA-205a and its target, the adhesion molecule Cadherin-11 (CDH11), in avian embryonic models. We demonstrate that CDH11 functions as a positive regulator of chondrocyte differentiation by promoting Wnt/β-catenin signaling. Conversely, miR-205a acts as a potent endogenous inhibitor of this process. Through dual-luciferase reporter assays, we confirm that miR-205a directly binds to the 3’UTR of CDH11 mRNA. Functional studies revealed that miR-205a overexpression suppresses chondrogenesis by downregulating CDH11, thereby inhibiting the Wnt/β-catenin pathway and key chondrogenic markers like Runx2 and BMP2. Silencing miR-205a or overexpressing CDH11 produced the opposite effect, promoting the differentiation program. Critically, rescue experiments using a Wnt/β-catenin pathway agonist substantiated that miR-205a exerts its inhibitory effects primarily through modulating this pathway. Our findings delineate a conserved miR-205a/CDH11/Wnt-β-catenin regulatory circuit that is essential for chondrocyte differentiation, offering fundamental new insights into the molecular etiology of cartilage development and its associated disorders.

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