871
Views
7
CrossRef citations to date
0
Altmetric
Addendum

From an orphan disease to a generalized molecular mechanism

PTPN11 loss-of-function mutations in the pathogenesis of metachondromatosis

&
Article: e26657 | Received 26 Aug 2013, Accepted 30 Sep 2013, Published online: 02 Oct 2013
 

Abstract

Recently, loss-of-function mutations in PTPN11 were linked to the cartilage tumor syndrome metachondromatosis (MC), a rare inherited disorder featuring osteochondromas, endochondromas and skeletal deformation. However, the underlying molecular and cellular mechanism for MC remained incompletely understood. By studying the role of the Src homology-2 domain-containing protein tyrosine phosphatase Shp2 (encoded by mouse Ptpn11) in cathepsin K-expressing cells, we identified a novel cell population in the perichondrial groove of Ranvier. In the absence of Shp2, these cells exhibit elevated Indian hedgehog (Ihh) signaling, proliferate excessively and cause ectopic cartilage formation and tumors. Our findings establish a critical role for a protein-tyrosine phosphatase (PTP) family member, in addition to the well-known roles of receptor tyrosine kinases (RTKs), in cartilage development and homeostasis. However, whether Shp2 deficiency in other epiphyseal chondroid cells and whether signaling pathways in addition to the IHH/Parathyroid Hormone–related Peptide (PTHrP) axis attribute to the formation of enchondromas and osteochondromas remains elusive. Understanding how chondrogenic events are regulated by SHP2 could aid in the development of novel therapeutic approaches to prevent and treat cartilage diseases, such as MC and osteoarthritis (OA).

This article refers to:

http:dx.doi.org/10.4161/rdis.26657

Disclosure of Potential Conflicts of Interest

No potential conflict of interest was disclosed.

Acknowledgments

We thank Dr Richard M Terek for review of the manuscript. This publication was made possible by the National Institutes of Health (NIH) and the National Institute for General Medicine Sciences (NIGMS) grant no. 8P20GM103468. This work was also funded by NIH R21AR57156 (to Yang W) and R37 CA49132 (to Neel BG), the Rhode Island Hospital Orthopedic Foundation and a grant from the Pediatric Orthopedic Society of North America and the Orthopedic Research and Education Foundation (to Yang W). Neel BG is a Canada Research Chair, Tier 1, and is also supported in part by the Ontario Ministry of Health and Long-term Care and the Princess Margaret Cancer Foundation.