Division of Biology and Medicine, Department of Molecular Microbiology and Immunology, Brown University Alpert Medical School, Providence, RI, 02912, USA.
Department of Orthopaedics, Rhode Island Hospital and Brown University Alpert Medical School, Providence, RI, USA.
Sci Rep. 2021 Oct 8;11(1):20006. doi: 10.1038/s41598-021-99339-0.
Due to redundancy with other tyrosine phosphatases, the ubiquitously expressed tyrosine phosphatase SHP-2 (encoded by Ptpn11) is not required for T cell development. However, Ptpn11 gene deletion driven by CD4 Cre recombinase leads to cartilage tumors in the wrist. Using a fate mapping system, we demonstrate that wrist tumor development correlates with increased frequency and numbers of non-hematopoietic lineage negative CD45 negative cells with a bone chondrocyte stromal cell precursor cell (BCSP) phenotype. Importantly, the BCSP subset has a history of CD4 expression and a marked wrist location tropism, explaining why the wrist is the main site of tumor development. Mechanistically, we found that in SHP-2 absence, SOX-9 is no longer regulated, leading to an uncontrolled proliferation of the BCSP subset. Altogether, these results identify a unique subset of chondrocyte precursors tightly regulated by SHP-2. These findings underscore the need for the development of methods to therapeutically target this subset of cells, which could potentially have an impact on treatment of SHP-2 dysfunction linked debilitating diseases.
由于与其他酪氨酸磷酸酶存在冗余，广泛表达的酪氨酸磷酸酶 SHP-2（由 Ptpn11 编码）对于 T 细胞发育并非必需。然而，由 CD4 Cre 重组酶驱动的 Ptpn11 基因缺失会导致手腕软骨瘤。使用命运图谱系统，我们证明手腕肿瘤的发展与非造血谱系阴性 CD45 阴性细胞的频率和数量增加相关，这些细胞具有骨软骨细胞基质细胞前体细胞（BCSP）表型。重要的是，BCSP 亚群具有 CD4 表达的历史和明显的手腕位置趋向性，这解释了为什么手腕是肿瘤发展的主要部位。从机制上讲，我们发现 SHP-2 缺失后，SOX-9 不再受到调控，导致 BCSP 亚群的不受控制增殖。总之，这些结果确定了 SHP-2 严格调控的独特软骨细胞前体细胞亚群。这些发现强调了需要开发针对该细胞亚群的治疗方法的必要性，这可能对治疗与 SHP-2 功能障碍相关的衰弱性疾病产生影响。
