Abstract
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.
Highlights
The formation of the cartilage anlage, its subsequent differentiation into mature chondrocytes, and the ultimate transdifferentiation of hypertrophic chondrocytes into functioning osteoblasts all depend on signals evoked by growth factors and other regulatory peptides[11,12], though cell-cell, and cell-matrix interactions are important[13,14]
Breeders for the SHP2 ablation in chondrocytes were generated by crossing mice bearing a single Ptpn[11] floxed allele (Ptpn11fl/+) to transgenic mice in which Cre expression is under the control of Col2α155,57 or Col10α1 promoter[56]
Phenotypic characterization showed that mice lacking SHP2 in the hypertrophic chondrocytes appeared normal through 10 weeks of age with the exception of a slight decrease in bone mineral density
Summary
The formation of the cartilage anlage, its subsequent differentiation into mature chondrocytes, and the ultimate transdifferentiation of hypertrophic chondrocytes into functioning osteoblasts all depend on signals evoked by growth factors and other regulatory peptides[11,12], though cell-cell, and cell-matrix interactions are important[13,14]. The exact molecular signals controlling these processes remain incompletely understood, the coordinated activation of sequential signaling pathways involving FGF, WNT/β-CATENIN, hedgehog, and BMP have been shown to be crucial[20,21,22,23,24,25,26,27] Understanding how these signaling pathways are regulated will provide insight into skeletal development and the treatment of disease. Removal of β-CATENIN from hypertrophic chondrocytes impairs their osteogenic differentiation and trabecular bone formation, while sustained β-CATENIN activation leads to enhanced bone mineralization[49] This suggests that β-CATENIN signaling is crucial for the transdifferentiation of hypertrophic chondrocytes. Characterization of the skeletal phenotype of mice lacking SHP2 in COL2α1- and COL10α1-expressing cells led to the discovery of SHP2 as an important regulator of chondrocyte proliferation, maturation, and differentiation to bone forming osteoblasts
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