SHP2 regulates skeletal cell fate by modifying SOX9 expression and transcriptional activity

Abstract

Chondrocytes and osteoblasts differentiate from a common mesenchymal precursor, the osteochondroprogenitor (OCP), and help build the vertebrate skeleton. The signaling pathways that control lineage commitment for OCPs are incompletely understood. We asked whether the ubiquitously expressed protein-tyrosine phosphatase SHP2 (encoded by Ptpn11) affects skeletal lineage commitment by conditionally deleting Ptpn11 in mouse limb and head mesenchyme using “Cre-loxP”-mediated gene excision. SHP2-deficient mice have increased cartilage mass and deficient ossification, suggesting that SHP2-deficient OCPs become chondrocytes and not osteoblasts. Consistent with these observations, the expression of the master chondrogenic transcription factor SOX9 and its target genes Acan, Col2a1, and Col10a1 were increased in SHP2-deficient chondrocytes, as revealed by gene expression arrays, qRT-PCR, in situ hybridization, and immunostaining. Mechanistic studies demonstrate that SHP2 regulates OCP fate determination via the phosphorylation and SUMOylation of SOX9, mediated at least in part via the PKA signaling pathway. Our data indicate that SHP2 is critical for skeletal cell lineage differentiation and could thus be a pharmacologic target for bone and cartilage regeneration.

Chondrogenesis: SHP2 regulates skeletal cell fate

The enzyme SHP2 is critical for the differentiation of skeletal cells and could be a pharmacological target for bone and cartilage regeneration. Osteo-chondroprogenitor cells arise from stem cells in the bone marrow and can differentiate into either osteoblasts (bone-producing cells) or chondrocytes (cartilage cells). A team headed by Wentian Yang at Brown University, Rhode Island found that mice deficient in SHP2 had increased cartilage mass and decreased ossification. As a result of SHP2 deficiency, abnormal cartilage growth developed at sites where mineralized bone would normally form. The team’s findings suggest that SHP2-deficient osteo-chondroprogenitor cells become chondrocytes, not osteoblasts. The authors believe that the ability to therapeutically manipulate cell fate by regulating SHP2 activity offers a new means of controlling cartilage formation in patients with various cartilage-related disorders, including tumors and osteoarthritis.

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