SHP2 Regulates Chondrocyte Terminal Differentiation, Growth Plate Architecture and Skeletal Cell Fates

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Patients with the inherited disorder, metachondromatosis (MC), develop multiple benign cartilage tumors during childhood. MC patients carry heterozygous loss-of-function mutations in the PTPN11 gene, and their cartilage tumors likely arise when the second PTPN11 allele is lost due to a somatic mutation. PTPN11 encodes a phosphatase called SHP2 that is involved in a variety of signaling pathways. Here, we use mouse models and cell culture assays to investigate the mechanisms by which loss of SHP2 promotes cartilage tumor formation. We show that cartilage tumors that form inside bones (enchondromas) likely arise due to disorganized growth and delayed terminal differentiation of growth plate chondrocytes, while cartilage tumors that form on the bone surface (exostoses) can arise due to ectopic chondrogenesis of fibroblast-like cells that surround bones. We also suggest that paracrine signals from SHP2-deficient cells cause neighboring SHP2-sufficient cells to contribute to exostoses and enchondromas. Finally, we provide in vitro data that the ERK1/2 pathway is regulated by SHP2 and promotes chondrocyte terminal differentiation. Together, our data provide insight into the mechanisms underlying cartilage tumor formation and implicate SHP2 as a key regulator of chondrocyte specification, organization and maturation.

Vyšlo v časopise: SHP2 Regulates Chondrocyte Terminal Differentiation, Growth Plate Architecture and Skeletal Cell Fates. PLoS Genet 10(5): e32767. doi:10.1371/journal.pgen.1004364
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004364

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