Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Ministry of Education, Shanghai, China.
Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Elife. 2019 Sep 4;8:e50208. doi: 10.7554/eLife.50208.
Indian Hedgehog (IHH) signaling, a key regulator of skeletal development, is highly activated in cartilage and bone tumors. Yet deletion of , encoding an inhibitor of IHH receptor Smoothened (SMO), in chondrocyte or osteoblasts does not cause tumorigenesis. Here, we show that deletion in mice Prrx1mesenchymal stem/stromal cells (MSCs) promotes MSC proliferation and osteogenic and chondrogenic differentiation but inhibits adipogenic differentiation. Moreover, deletion led to development of osteoarthritis-like phenotypes, exostoses, enchondroma, and osteosarcoma in Smo-Gli1/2-dependent manners. The cartilage and bone tumors are originated from Prrx1 lineage cells and express low levels of osteoblast and chondrocyte markers, respectively. Mechanistically, deletion increases the expression of Wnt5a/6 and leads to enhanced β-Catenin activation. Inhibiting Wnt/β-Catenin pathway suppresses development of skeletal anomalies including enchondroma and osteosarcoma. These findings suggest that cartilage/bone tumors arise from their early progenitor cells and identify the Wnt/β-Catenin pathway as a pharmacological target for cartilage/bone neoplasms.
印度刺猬 (IHH) 信号通路是骨骼发育的关键调节因子，在软骨和骨肿瘤中高度激活。然而，编码 IHH 受体 Smoothened (SMO) 抑制剂的基因缺失，在软骨细胞或成骨细胞中并不会导致肿瘤发生。在这里，我们发现，在小鼠 Prrx1 间充质干细胞/基质细胞 (MSCs) 中缺失会促进 MSC 的增殖以及成骨和成软骨分化，但抑制脂肪生成分化。此外，缺失导致 Smo-Gli1/2 依赖性的骨关节炎样表型、外生骨疣、软骨瘤和骨肉瘤的发生。这些软骨和骨肿瘤来源于 Prrx1 谱系细胞，分别表达低水平的成骨细胞和软骨细胞标志物。在机制上，缺失会增加 Wnt5a/6 的表达，并导致 β-Catenin 激活增强。抑制 Wnt/β-Catenin 通路会抑制包括软骨瘤和骨肉瘤在内的骨骼异常的发生。这些发现表明，软骨/骨肿瘤起源于其早期祖细胞，并确定 Wnt/β-Catenin 通路是软骨/骨肿瘤的一个药物靶点。
