Wang Lijun, Yang Huiliang, Huang Jiahui, Pei Shaopeng, Wang Liyun, Feng Jian Q, Jing Dian, Zhao Hu, Kronenberg Henry M, Moore Douglas C, Yang Wentian
Department of Orthopedic Surgery, Brown University Alpert Medical School and Rhode Island Hospital, Providence, RI, 02903, USA.
Department of Mechanical Engineering, University of Delaware, Newark, DE, DE19716, USA.
Bone Res. 2021 Jan 27;9(1):6. doi: 10.1038/s41413-020-00129-7.
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依赖于信号蛋白的可逆磷酸化。迄今为止，关于成骨细胞的大多数研究工作都集中在酪氨酸激酶介导的磷酸化上，而关于蛋白酪氨酸磷酸酶（PTPases）介导的去磷酸化的研究却很少。SHP2（由PTPN11编码）是一种广泛表达的PTPase。PTPN11突变与努南综合征（NS）和软骨瘤病（MC）患者的骨骼和软骨表现有关，但其潜在机制仍不清楚。在这里，我们报告称，在表达骨γ-羧基谷氨酸蛋白（Bglap）的骨细胞中缺失SHP2会导致小梁骨和皮质骨出现大量骨质减少，这是由于骨细胞成熟失败和破骨细胞活性增强所致；而在Bglap软骨细胞中缺失SHP2会导致老年小鼠出现内生软骨瘤和骨软骨瘤，并伴有管状骨长度增加。从机制上讲，发现SHP2通过促进RUNX2/OSTERIX信号传导来促进成骨细胞分化，并通过抑制成骨细胞和骨细胞中STAT3介导的RANKL产生来抑制破骨细胞生成。这些发现可能有助于解释NS和MC患者骨骼系统受损的原因，并为开发治疗骨骼疾病的新型疗法提供依据。
