Activation of hedgehog signaling in mesenchymal stem cells induces cartilage and bone tumor formation via Wnt/β-Catenin

eLife

Jiajia Liu¹  Lin He¹  Manju Che¹  Soma Biswas¹  Baojie Li¹  Huijuan Liu¹  Ping Li¹  Qi Deng¹  Gang Ma¹  Yingzi Yang²  Zhenlin Zhang³  Zhanying Wei³ 

[1] Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Ministry of Education, Shanghai, China;Department of Developmental Biology, Harvard School of Dental Medicine, Boston, United States;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;

关键词: hedgehog;    bone tumor;    mesenchymal stem cell;   

DOI  :  10.7554/eLife.50208

来源: DOAJ

【 摘 要 】

Indian Hedgehog (IHH) signaling, a key regulator of skeletal development, is highly activated in cartilage and bone tumors. Yet deletion of Ptch1, encoding an inhibitor of IHH receptor Smoothened (SMO), in chondrocyte or osteoblasts does not cause tumorigenesis. Here, we show that Ptch1 deletion in mice Prrx1+mesenchymal stem/stromal cells (MSCs) promotes MSC proliferation and osteogenic and chondrogenic differentiation but inhibits adipogenic differentiation. Moreover, Ptch1 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, Ptch1 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.

【 授权许可】

Unknown