Ptpn11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling

Abstract

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.

SHP2-Deficiency in Chondrocytes Deforms Orofacial Cartilage and Ciliogenesis in Mice

“…1Q-T). (7,9) These results suggest that disruption of Shp2 morphologically deformed the mandibular condyle shape, presumably due to the disorganization of cartilage layers, the expansion of cartilage nodules into the trabecular bone, and the alteration of chondrocyte cell fate.…”

“…(3) These skeletal phenotypes (ie, scoliosis, metachondromatosis) are reproduced in Shp2-deleted mice. (2,(4)(5)(6)(7)(8)(9) Column formation of the growth plate cartilage in the hypertrophic chondrocyte layer in the metaphysis is severely affected in Shp2 mutant mice, suggesting that SHP2 plays an important role in cartilage and chondrocyte formation. Noonan and LEOPARD syndromes develop characteristic facial features including short and broad nose, small chin, and retardation of dental development.…”

IGF-1 regulation of key signaling pathways in bone

“…Recent studies have shown that the cells adjacent to the zone of Ranvier in the perichondrium harbor progenitor cells. 44 Targeting osteoprogenitor-specific IGF-1 and IGF1R deletion utilizing Prrx1cre, Dermo1cre or cathepsin K cre (shown to be expressed in the perichondrial groove of Ranvier) 45 to study the role of IGF-1 in early mesenchymal cells would be important. This will enable us to understand the role of IGF-1 in regulating pathways important for early bone formation and also to identify if this signaling pathway has a role in regulating chondro/osteo progenitor cells.…”

A Novel Phosphatidic Acid-Protein-tyrosine Phosphatase D2 Axis Is Essential for ERBB2 Signaling in Mammary Epithelial Cells

“…SHP2 plays a well characterized oncogenic role as an activator of RAS signaling in a variety of tumors (3). However, deficiency of PTPN11, the gene that encodes SHP2, has also been shown to underlie excessive proliferation in cartilage tumors, consistent with a tumor suppressor function in this context (51).…”