Li Yang, Yang Shuting, Qin Ling, Yang Shuying
Department of Basic & Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Department of Orthopedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Cell Discov. 2021 Apr 20;7(1):26. doi: 10.1038/s41421-021-00254-5.
Chondrogenesis is a major contributor to skeletal development and maintenance, as well as bone repair. Transcriptional coactivator with PDZ-binding motif (TAZ) is a key regulator of osteogenesis and adipogenesis, but how TAZ regulates chondrogenesis and skeletal development remains undefined. Here, we found that TAZ expression is gradually increased during chondrogenic differentiation. Deletion of TAZ in chondrocyte lineage impaired articular and growth plate, as well as the bone development in TAZ-deficient mice. Consistently, loss of TAZ impaired fracture healing. Mechanistically, we found that ectopic expression of TAZ markedly promoted chondroprogenitor proliferation, while deletion of TAZ impaired chondrocyte proliferation and differentiation. TAZ associated with Sox5 to regulate the expression and stability of Sox5 and downstream chondrocyte marker genes' expression. In addition, overexpression of TAZ enhanced Col10a1 expression and promoted chondrocyte maturation, which was blocked by deletion of TAZ. Overall, our findings demonstrated that TAZ is required for skeletal development and joint maintenance that provided new insights into therapeutic strategies for fracture healing, heterotopic ossification, osteoarthritis, and other bone diseases.
软骨形成是骨骼发育、维持以及骨修复的主要促成因素。含PDZ结合基序的转录共激活因子（TAZ）是成骨和成脂的关键调节因子，但TAZ如何调节软骨形成和骨骼发育仍不清楚。在此，我们发现TAZ的表达在软骨分化过程中逐渐增加。软骨细胞谱系中TAZ的缺失会损害关节和生长板，以及TAZ缺陷小鼠的骨骼发育。同样，TAZ的缺失会损害骨折愈合。从机制上来说，我们发现TAZ的异位表达显著促进软骨祖细胞增殖，而TAZ的缺失则损害软骨细胞增殖和分化。TAZ与Sox5结合以调节Sox5的表达和稳定性以及下游软骨细胞标记基因的表达。此外，TAZ的过表达增强了Col10a1的表达并促进软骨细胞成熟，而TAZ的缺失则会阻断这一过程。总体而言，我们的研究结果表明TAZ是骨骼发育和关节维持所必需的，这为骨折愈合、异位骨化、骨关节炎和其他骨骼疾病的治疗策略提供了新的见解。
