Targeted Ptpn11 deletion in mice reveals the essential role of SHP2 in osteoblast differentiation and skeletal homeostasis

The maturation and function of osteoblasts(OBs)rely heavily on the reversible phosphorylation of signaling proteins.To date,most of the work in OBs has focused on phosphorylation by tyrosyl kinases,but little has been revealed about dephosphorylation by protein tyrosine phosphatases(PTPases).SHP2(encoded by PTPN11)is a ubiquitously expressed PTPase.PTPN11 mutations are associated with both bone and cartilage manifestations in patients with Noonan syndrome(NS)and metachondromatosis(MC),although the underlying mechanisms remain elusive.Here,we report that SHP2 deletion in bone gamma-carboxyglutamate protein-expressing(Bglap+)bone cells leads to massive osteopenia in both trabecular and cortical bones due to the failure of bone cell maturation and enhanced osteoclast activity,and its deletion in Bglap+chondrocytes results in the onset of enchondroma and osteochondroma in aged mice with increased tubular bone length.Mechanistically,SHP2 was found to be required for osteoblastic differentiation by promoting RUNX2/OSTERIX signaling and for the suppression of osteoclastogenesis by inhibiting STAT3-mediated RANKL production by osteoblasts and osteocytes.These findings are likely to explain the compromised skeletal system in NS and MC patients and to inform the development of novel therapeutics to combat skeletal disorders.

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

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-lox P＂-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, q RT-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.