Targeted disruption of Shp2 in chondrocytes leads to metachondromatosis with multiple cartilaginous protrusions

Harry K W Kim, Gen Sheng Feng, Di Chen, Philip D. King, Nobuhiro Kamiya

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


Metachondromatosis is a benign bone disease predominantly observed in the hands and feet of children or young adults demonstrating two different manifestations: a cartilage-capped bony outgrowth on the surface of the bone called exostosis and ectopic cartilaginous nodules inside the bone called enchondroma. Recently, it has been reported that loss-of-function mutations of the SHP2 gene, which encodes the SHP2 protein tyrosine phosphatase, are associated with metachondromatosis. The purpose of this study was to investigate the role of SHP2 in postnatal cartilage development, which is largely unknown. We disrupted Shp2 during the postnatal stage of mouse development in a chondrocyte-specific manner using a tamoxifen-inducible system. We found tumor-like nodules on the hands and feet within a month after the initial induction. The SHP2-deficient mice demonstrated an exostosis-like and enchondroma-like phenotype in multiple bones of the hands, feet, and ribs as assessed by X-ray and micro-computed tomography (CT). Histological assessment revealed the disorganization of the growth plate cartilage, a cartilaginous protrusion from the epiphyseal bone, and ectopic cartilage nodules within the bones, which is consistent with the pathological features of metachondromatosis in humans (ie, both exostosis and enchondroma). At molecular levels, we observed an abundant expression of Indian hedgehog protein (IHH) and fibroblast growth factor 2 (FGF2) and impaired expression of mitogen-activated protein kinases (MAPK) in the affected cartilage nodules in the SHP2-deficient mice. In summary, we have generated a mouse model of metachondromatosis that includes manifestations of exostosis and enchondroma. This study provides a novel model for the investigation of the pathophysiology of the disease and advances the understanding of metachondromatosis. This model will be useful to identify molecular mechanisms for the disease cause and progression as well as to develop new therapeutic strategies in the future.

Original languageEnglish (US)
Pages (from-to)761-769
Number of pages9
JournalJournal of Bone and Mineral Research
Issue number3
StatePublished - Mar 2014


  • SHP2
  • cartilage-specific knock-out mouse
  • enchondroma
  • exostosis
  • metachondromatosis

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine


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