Department of Orthopaedic Surgery, Brown University Alpert Medical School, Providence, RI, 02903, USA.
Department of Endocrinology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, P.R. China.
Sci Rep. 2017 Oct 5;7(1):12699. doi: 10.1038/s41598-017-12767-9.
Transdifferentiation of hypertrophic chondrocytes into bone-forming osteoblasts has been reported, yet the underlying molecular mechanism remains incompletely understood. SHP2 is an ubiquitously expressed cytoplasmic protein tyrosine phosphatase. SHP2 loss-of-function mutations in chondroid cells are linked to metachondromatosis in humans and mice, suggesting a crucial role for SHP2 in the skeleton. However, the specific role of SHP2 in skeletal cells has not been elucidated. To approach this question, we ablated SHP2 in collagen 2α1(Col2α1)-Cre- and collagen 10α1(Col10α1)-Cre-expressing cells, predominantly proliferating and hypertrophic chondrocytes, using "Cre-loxP"-mediated gene excision. Mice lacking SHP2 in Col2α1-Cre-expressing cells die at mid-gestation. Postnatal SHP2 ablation in the same cell population caused dwarfism, chondrodysplasia and exostoses. In contrast, mice in which SHP2 was ablated in the Col10α1-Cre-expressing cells appeared normal but were osteopenic. Further mechanistic studies revealed that SHP2 exerted its influence partly by regulating the abundance of SOX9 in chondrocytes. Elevated and sustained SOX9 in SHP2-deficient hypertrophic chondrocytes impaired their differentiation to osteoblasts and impaired endochondral ossification. Our study uncovered an important role of SHP2 in bone development and cartilage homeostasis by influencing the osteogenic differentiation of hypertrophic chondrocytes and provided insight into the pathogenesis and potential treatment of skeletal diseases, such as osteopenia and osteoporosis.
肥大软骨细胞向成骨细胞的转分化已有报道，但潜在的分子机制尚不完全清楚。SHP2 是一种广泛表达的细胞质酪氨酸磷酸酶。软骨细胞中的 SHP2 功能丧失突变与人类和小鼠的软骨发育不良有关，这表明 SHP2 在骨骼中起着至关重要的作用。然而，SHP2 在骨骼细胞中的具体作用尚未阐明。为了研究这个问题，我们使用“Cre-loxP”介导的基因切除，在胶原 2α1(Col2α1)-Cre 和胶原 10α1(Col10α1)-Cre 表达细胞中（主要是增殖和肥大的软骨细胞）敲除 SHP2。缺乏 Col2α1-Cre 表达细胞中 SHP2 的小鼠在中期妊娠时死亡。在同一细胞群中敲除 SHP2 会导致出生后小鼠出现侏儒症、软骨发育不良和外生骨疣。相比之下，在 Col10α1-Cre 表达细胞中敲除 SHP2 的小鼠看起来正常，但骨密度降低。进一步的机制研究表明，SHP2 通过调节软骨细胞中 SOX9 的丰度来发挥其影响。在缺乏 SHP2 的肥大软骨细胞中，SOX9 水平升高且持续，损害了其向成骨细胞的分化，并损害了软骨内骨化。我们的研究揭示了 SHP2 通过影响肥大软骨细胞的成骨分化在骨骼发育和软骨稳态中的重要作用，并为骨骼疾病（如骨质疏松症）的发病机制和潜在治疗提供了新的见解。
