SHP2

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

"Metachondromatosis is a benign bone disease predominantly observed in 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{Can these cartilage nodules form new growth plates or be used to increase height?}. Loss-of-function mutations of the SHP2 gene, that encodes the SHP2 protein tyrosine phosphatase, are associated with metachondromatosis.  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-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 (i.e. both exostosis and enchondroma). At molecular levels, we observed an abundant expression of IHH (indian hedgehog protein) and FGF2 (fibroblast growth factor 2) and impaired expression of MAPK (mitogen-activated protein kinases) in the affected cartilage nodules in the SHP2-deficient mice."

"SHP2 (src homology-2)-containing protein tyrosine phosphate, also known as PTPN11 (Protein-tyrosine phosphatases non-receptor type 11) plays a central role in RAS/MAPK (mitogenactivated protein kinases) signaling downstream of several receptor tyrosine kinases including the EGFR (epidermal growth factor receptor) and FGFR (fibroblast growth factor receptor). In general, SHP2 promotes RAS/MAPK signal transduction downstream of growth factor receptors"

"we ablated[reduce] the Shp2 gene postnatally in all somatic cells of the body and found multiple skeletal abnormalities including scoliosis, kyphosis, osteopetrosis and growth plate disturbance with cartilage abnormalities"

"Two weeks after tamoxifen was first administered to the mice, visible nodule formations in the dorsal hands of the SHP2 cKO mice were observed. These nodules developed and grew under the skin over time until sacrifice of mice at 12 weeks of age"<-the nodules grew but they were not in the position to increase height.

"The nodules were found close to multiple hand joints including the metacarpal-phalangeal and the proximal interphalangeal joints."

"Upon closer examination, the nodules were seen to originate from the region between the perichondrium and periosteum that is named the groove of Ranvier"<-So the groove of Ranvier is key for neo-growth plate formation.

"In SHP2 cKO mice, the expression domain of IHH was elongated in the rib growth plate cartilage
compared with the controls"

"the IHH was abundantly expressed in the ectopic cartilaginous nodules in SHP2 cKO rib bones"