ZBTB20 Regulating Postnatal Articular Cartilage Development and Homeostasis: Implications for Early‐Onset Osteoarthritis

Objective Mutations in ZBTB20, a transcription factor, are linked to epiphyseal dysplasia and articular degeneration in humans. This study investigates the role of ZBTB20 in regulating articular cartilage growth and integrity during postnatal development and its implications for early‐onset osteoarthritis (OA) in mice. Methods We assessed the spatiotemporal expression of ZBTB20 in articular cartilage using immunostaining and generated an inducible cartilage‐specific Zbtb20 knockout mouse model. The impacts of Zbtb20 deletion on cartilage thickness, zonal organization, cellular proliferation, and apoptosis were analyzed. We employed histology, Micro‐CT, in situ hybridization, RNA‐sequencing, and CUT&Tag to evaluate structural and molecular changes in knees from six to eight male mice per group. ZBTB20 expression in human OA cartilage was analyzed using publicly available datasets. Results ZBTB20 was expressed in postnatal developing and adult articular chondrocytes. Postnatal Zbtb20 deletion resulted in progressive thickening of articular cartilage in knees, with a 1.9‐fold increase at 2 months of age, particularly in the deep and calcified zones. This was accompanied by chondrocyte overproliferation and differentiation defects, leading to early‐onset cartilage degeneration by 6 months. RNA‐sequencing and CUT&Tag analyses revealed that ZBTB20 directly regulates a broad set of genes essential for cartilage growth, chondrocyte differentiation, and extracellular matrix organization. Moreover, ZBTB20 expression was significantly reduced in aging‐related OA cartilage in both mice and humans, and inducible deletion of Zbtb20 in adult cartilage resulted in severe spontaneous OA‐like changes in mice. Conclusion ZBTB20 is essential for postnatal articular cartilage development and homeostasis, with a protective role in aging‐related OA progression. image