Division of Orthopaedic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA 19104.
Proc Natl Acad Sci U S A. 2021 Feb 23;118(8). doi: 10.1073/pnas.2019152118.
Cartilage is essential throughout vertebrate life. It starts developing in embryos when osteochondroprogenitor cells commit to chondrogenesis, activate a pancartilaginous program to form cartilaginous skeletal primordia, and also embrace a growth-plate program to drive skeletal growth or an articular program to build permanent joint cartilage. Various forms of cartilage malformation and degeneration diseases afflict humans, but underlying mechanisms are still incompletely understood and treatment options suboptimal. The transcription factor SOX9 is required for embryonic chondrogenesis, but its postnatal roles remain unclear, despite evidence that it is down-regulated in osteoarthritis and heterozygously inactivated in campomelic dysplasia, a severe skeletal dysplasia characterized postnatally by small stature and kyphoscoliosis. Using conditional knockout mice and high-throughput sequencing assays, we show here that SOX9 is required postnatally to prevent growth-plate closure and preosteoarthritic deterioration of articular cartilage. Its deficiency prompts growth-plate chondrocytes at all stages to swiftly reach a terminal/dedifferentiated stage marked by expression of chondrocyte-specific () and progenitor-specific ( and ) genes. Up-regulation of osteogenic genes (, , and ) and overt osteoblastogenesis quickly ensue. SOX9 deficiency does not perturb the articular program, except in load-bearing regions, where it also provokes chondrocyte-to-osteoblast conversion via a progenitor stage. Pathway analyses support roles for SOX9 in controlling TGFβ and BMP signaling activities during this cell lineage transition. Altogether, these findings deepen our current understanding of the cellular and molecular mechanisms that specifically ensure lifelong growth-plate and articular cartilage vigor by identifying osteogenic plasticity of growth-plate and articular chondrocytes and a SOX9-countered chondrocyte dedifferentiation/osteoblast redifferentiation process.
软骨是脊椎动物生命中必不可少的。当骨软骨祖细胞开始向软骨生成分化，激活全面软骨形成程序，形成软骨骨骼原基，同时也采用生长板程序或关节程序来驱动骨骼生长或构建永久性关节软骨时，胚胎中的软骨就开始发育了。各种形式的软骨畸形和退行性疾病折磨着人类，但潜在的机制仍不完全清楚，治疗选择也不理想。转录因子 SOX9 是胚胎软骨生成所必需的，但它的出生后作用仍不清楚，尽管有证据表明它在骨关节炎中下调，在 camptomelic 发育不良中杂合失活，camptomelic 发育不良是一种严重的骨骼发育不良，出生后表现为身材矮小和脊柱侧凸。使用条件性敲除小鼠和高通量测序分析，我们在这里表明 SOX9 出生后需要防止生长板闭合和关节软骨发生前骨关节炎恶化。它的缺乏促使所有阶段的生长板软骨细胞迅速达到一个终末/去分化阶段，其特征是表达软骨细胞特异性（）和祖细胞特异性（和）基因。成骨基因（、、和）的上调和明显的成骨细胞发生很快随之发生。SOX9 缺乏不会扰乱关节程序，除了在承重区域，在那里它还通过祖细胞阶段引发软骨细胞向成骨细胞的转化。通路分析支持 SOX9 在控制 TGFβ和 BMP 信号活动中的作用，在此细胞谱系转化过程中。总之，这些发现通过确定生长板和关节软骨的成骨可塑性以及 SOX9 对抗的软骨细胞去分化/成骨细胞再分化过程，加深了我们对确保终身生长板和关节软骨活力的细胞和分子机制的现有理解。
