Activation of Hedgehog Signaling in Mesenchymal Stem Cells Induces Cartilage and Bone Tumor Formation Via Wnt/β-Catenin

Overview

Journal Elife

Specialty Biology

Date 2019 Sep 5

PMID 31482846

Citations 59

Authors

Qi Deng

Ping Li

Manju Che

Jiajia Liu

Soma Biswas

Gang Ma

Lin He

Zhanying Wei

Zhenlin Zhang

Yingzi Yang

Huijuan Liu

Baojie Li

Affiliations

Soon will be listed here.

Abstract

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.

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