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).