SHP2, encoded by PTPN11, is required for survival, proliferation and differentiation of various cell types1,2. Germ line activating mutations in PTPN11 cause Noonan Syndrome, while somatic PTPN11 mutations cause childhood myeloproliferative disease and contribute to some solid tumors. Recently, heterozygous inactivating mutations in PTPN11 were found in metachondromatosis, a rare inherited disorder featuring multiple exostoses, endochondromas, joint destruction and bony deformities3,4. The detailed pathogenesis of this disorder has remained unclear. Here, we used a conditional knockout allele (Ptpn11fl) and Cre recombinase (Cre) transgenic mice to delete Ptpn11 specifically in monocytes, macrophages and osteoclasts (lysozyme M-Cre; LysMCre) or in cathepsin K (Ctsk)-expressing cells, previously thought to be osteoclasts. LysMCre;Ptpn11fl/fl mice had mild osteopetrosis. Surprisingly, however, CtskCre;Ptpn11fl/fl mice developed features strikingly similar to metachondromatosis. Lineage tracing revealed a novel population of Ctsk-Cre-expressing cells in the “Perichondrial Groove of Ranvier” that display markers and functional properties consistent with mesenchymal progenitors. Chondroid neoplasms arose from these cells and showed decreased Erk activation, increased Indian Hedgehog (Ihh) and Parathyroid hormone-related protein (Pthrp) expression and excessive proliferation. Shp2-deficient chondroprogenitors had decreased FGF-evoked Erk activation and enhanced Ihh and Pthrp expression, whereas FGFR or MEK inhibitor treatment of chondroid cells increased Ihh and Pthrp expression. Most importantly, Smoothened inhibitor treatment ameliorated metachondromatosis features in CtskCre;Ptpn11fl/fl mice. Thus, in contrast to its pro-oncogenic role in hematopoietic and epithelial cells, Ptpn11 is a tumor suppressor in cartilage, acting via an FGFR/MEK/ERK-dependent pathway in a novel progenitor cell population to prevent excessive Ihh production.

The dart thrower's path defined the transition between flexion and extension rotation of the scaphoid and lunate, and it identified wrist positions at which scaphoid and lunate motion approached zero. These findings indicate that this path of wrist motion confers a unique degree of radiocarpal stability and suggests that this direction, rather than the anatomical directions of wrist flexion-extension and radioulnar deviation, is the primary functional direction of the radiocarpal joint.

The in situ-setting calcium phosphate cement investigated in this study compared favorably with polymethylmethacrylate in a single-cycle, pull-out test of augmented pedicle screws in senile trabecular bone. With further evaluation, this cement may offer an alternative to polymethylmethacrylate for the enhancement of pedicle screw fixation clinically.