Editors' ChoiceDevelopment

Discovery of Cartilage-Forming Stem Cells

Sci. Signal.  30 Jul 2013:
Vol. 6, Issue 286, pp. ec176
DOI: 10.1126/scisignal.2004553

The tyrosine phosphatase Shp2, encoded by PTPN11 in humans, is associated with various forms of blood cell cancer and syndromes associated with aberrant signaling through the Ras–mitogen-activated protein kinase (MAPK) pathway. Inactivating mutations in PTPN11 also cause metachondromatosis, a bone disorder associated with excess bone formation (see Zaidi and Méndez-Ferrer). To investigate the mechanism by which loss of Shp2 function leads to metachondromatosis, Yang et al. engineered mice with a selective knockout (KO) of Shp2 in different sets of bone-associated cells. The LysM-KO animals lacked Shp2 in monocytes, macrophages, and osteoclast precursor cells, whereas the Cstk-KO mice lacked Shp2 in mature osteoclasts. Although the LysM-KO mice developed mild age-related osteopetrosis (an increase in bone density), the Cstk-KO mice developed many of the skeletal abnormalities seen in patients with metachondromatosis, including benign cartilage tumors. Lineage-tracing studies revealed that the Cstk-Cre reporter was expressed in a subset of perichondrial cells in the groove of Ranvier, and analysis of knee joint sections from the Cstk-KO mice showed an expansion of cells in the groove of Ranvier. Using yellow fluorescent protein (YFP) to tag the Cstk-KO cells, the bone lesions and most of the chondroid tumor cells in the Cstk-KO mice were found to consist of YFP+ chondroid cells at various developmental stages. Flow cytometry showed that within the YFP+ cell population, there were increased numbers of cells with mesenchymal progenitor markers, and, when cultured in vitro, these cells were able to differentiate into multiple different types of cells. Thus, these appear to represent a previously uncharacterized chondroid progenitor stem cell. Transcript analysis from the tumors from the Cstk-KO mice indicated that messenger RNAs encoding Indian hedgehog (Ihh) and parathyroid hormone-related protein (Pthrp) were increased. Shp2 activity is necessary for fibroblast growth factor 18 (Fgf18) to activate the Ras-MAPK-ERK (extracellular signal–regulated kinase) pathway and inhibit Ihh expression, and ERK signaling was decreased in the Cstk-KO progenitor cells. Treatment of the Cstk-KO mice with an inhibitor of the Hedgehog pathway reduced the severity of the skeletal overgrowth and improved mobility. Thus, this study identified a cartilage stem cell population that in the absence of functional Shp2 can become a source of benign bone tumors. In addition, this study delineated a pathway through which loss of Shp2 triggered excessive proliferation of these stem cells and showed that targeting Ihh signaling was an effective strategy for ameliorating symptoms.

W. Yang, J. Wang, D. C. Moore, H. Liang, M. Dooner, Q. Wi, R. Terek, Q. Chen, M. G. Ehrlich, P. J. Quesenberry, B. G. Neel, Ptpb11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling. Nature 499, 491–495 (2013). [PubMed]

M. Zaidi, S. Méndez-Ferrer, Tumour stem cells in bone. Nature 499, 414–416 (2013). [Online Journal]