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.

成骨细胞（OBs）的成熟和功能在很大程度上取决于信号蛋白的可逆磷酸化。迄今为止，OB中的大部分工作都集中在酪氨酸激酶的磷酸化上，但是关于蛋白质酪氨酸磷酸酶（PTPases）的去磷酸化作用却鲜有报道。SHP2（由PTPN11编码）是一个普遍表达的PTPase。PTPN11突变与Noonan综合征（NS）和metachondromatosis（MC）的患者的骨和软骨表现均相关，尽管其潜在机制尚不清楚。在这里，我们报告说SHP2缺失在骨γ-羧基谷氨酸蛋白表达（Bglap ⁺）由于骨细胞成熟的失败和破骨细胞活性的增强，骨细胞导致小梁和皮质骨均发生大量骨质减少，而Bglap ⁺软骨细胞中的骨细胞缺失会导致老年小鼠的内生软骨瘤和骨软骨瘤发作，并增加管状骨长度。从机理上讲，SHP2被认为是通过促进RUNX2 / OSTERIX信号来进行成骨细胞分化，并通过抑制成骨细胞和成骨细胞产生的STAT3介导的RANKL来抑制成骨细胞生成。这些发现可能可以解释NS和MC患者的骨骼系统受损，并为对抗骨骼疾病的新型疗法的发展提供信息。