Deletion of Ptpn11 in a newly defined mesenchymal progenitor population in the perichondral groove of Ranvier leads to metachondromatosis by increasing Indian hedgehog expression and activating hedgehog signalling, a process that can be reversed with the use of hedgehog pathway inhibitors. Inactivation of PTPN11, which encodes the phosphatase SHP2, is the cause of the inherited cartilage tumour disorder metachondromatosis. Using a mouse model, Wentian Yang and colleagues show that deletion of the Ptpn11 gene in osteoclasts leads to metachondromatosis that originates in a newly identified mesenchymal progenitor population in the perichondrial groove of Ranvier. Ptpn11 loss acts by activating hedgehog signalling, and metachondromatosis can be ameliorated in this model by hedgehog pathway inhibitors. Therefore in contrast to other tumour types where it promotes tumour formation, Ptpn11 suppresses tumorigenesis in cartilage tissue. The tyrosine phosphatase SHP2, encoded by PTPN11, is required for the survival, proliferation and differentiation of various cell types1,2. Germline activating mutations in PTPN11 cause Noonan syndrome, whereas somatic PTPN11 mutations cause childhood myeloproliferative disease and contribute to some solid tumours. Recently, heterozygous inactivating mutations in PTPN11 were found in metachondromatosis, a rare inherited disorder featuring multiple exostoses, enchondromas, joint destruction and bony deformities3,4. The detailed pathogenesis of this disorder has remained unclear. Here we use a conditional knockout (floxed) Ptpn11 allele (Ptpn11fl) and Cre recombinase 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. Notably, however, CtskCre;Ptpn11fl/fl mice developed features very similar to metachondromatosis. Lineage tracing revealed a novel population of CtskCre-expressing cells in the perichondrial groove of Ranvier that display markers and functional properties consistent with mesenchymal progenitors. Chondroid neoplasms arise from these cells and show decreased extracellular signal-regulated kinase (ERK) pathway activation, increased Indian hedgehog (Ihh) and parathyroid hormone-related protein (Pthrp, also known as Pthlh) expression and excessive proliferation. Shp2-deficient chondroprogenitors had decreased fibroblast growth factor-evoked ERK activation and enhanced Ihh and Pthrp expression, whereas fibroblast growth factor receptor (FGFR) or mitogen-activated protein kinase kinase (MEK) inhibitor treatment of chondroid cells increased Ihh and Pthrp expression. Importantly, smoothened inhibitor treatment ameliorated metachondromatosis features in CtskCre;Ptpn11fl/fl mice. Thus, in contrast to its pro-oncogenic role in haematopoietic and epithelial cells, Ptpn11 is a tumour suppressor in cartilage, acting through a FGFR/MEK/ERK-dependent pathway in a novel progenitor cell population to prevent excessive Ihh production.

Study is to compare CT-based structural rigidity analysis (CTRA) with physician-derived Mirels scoring for predicting pathologic fracture in femoral bone lesions. We hypothesized CTRA would be superior to Mirels in predicting fracture risk within the first year based on (1) sensitivity, specificity, positive predictive value, and negative predictive value; (2) receiver operator characteristic (ROC) analysis; and (3) fracture prediction after controlling for potential confounding variables such as age and lesion size. Methods Consented patients with femoral metastatic lesions were assigned Mirels scores by the individual enrolling orthopaedic oncologist based on plain radiographs and then underwent CT scans of both femurs with a phantom of known density. The CTRA was then performed. Between 2004 and 2008, six study centers performed CTRA on 125 patients. The general indications for this test were femoral metastatic lesions potentially at risk of fracture. The enrolling physician was allowed the choice of prophylactic stabilization or nonsurgical treatment, and the local treating oncology team along with the patient made this decision. Of those 125 patients, 78 (62%) did not undergo prophylactic stabilization and had followup sufficient for inclusion, which was fracture through the lesion within 12 months of CTRA, death within 12 months of CTRA, or 12-month survival after CTRA without fracture, whereas 15 (12%) were lost to followup and could not be studied here. The mean patient age was 61 years (SD, 14 years). There were 46 women. Sixty-four of the lesions were located in the proximal femur, 13 were in the diaphysis, and four were distal. Osteolytic lesions prevailed (48 lesions) over mixed (31 lesions) and osteoblastic (15 lesions). The most common primary cancers were breast (25 lesions), lung (14 lesions), and myeloma (11 lesions). CTRA was compared with Mirels based on sensitivity/specificity analysis, ROC, and fracture prediction by multivariate analysis. For the CTRA, reduction greater than 35% in axial, bending, or torsional rigidities at the lesion was considered at risk for fracture, whereas a Mirels score of 9 or above, as suggested in the original manuscript, was used as the definition of impending fracture. Results CTRA provided higher sensitivity (100% versus 66.7%), specificity (60.6% versus 47.9%), positive predictive value (17.6% versus 9.8%), and negative predictive value (100% versus 94.4%) compared with the classic Mirels definition of impending fracture (≥ 9), although there was considerable overlap in the confidence intervals. ROC curve analysis found CTRA to be better than the Mirels score regardless of what Mirels score cutoff was used. After controlling for potential confounding variables including age, lesion size, and Mirels scores, multivariable logistic regression indicated that CTRA was a better predictor of fracture (likelihood ratio test = 10.49, p < 0.001). Conclusions CT-based structural rigidity analysis is better than Mirels score in predicting femoral impending pathologic fracture. CTRA appears to provide a substantial advance in the accuracy of predicting pathological femur fracture over currently used clinical and radiographic criteria. Level of Evidence Level III, diagnostic study....

Objective: To determine if supplemental intraarticular α₂‐macroglobulin (α₂M) has a chondroprotective effect in a rat model of osteoarthritis (OA).Methods: Using Western blotting, mass spectrometry, enzyme‐linked immunosorbent assay (ELISA), and immunohistochemistry, α₂M was identified as a potential therapeutic agent through a comparison of α₂M concentrations in serum, synovial fluid (SF), and cartilage from normal subjects and patients with OA. In cultured chondrocytes, the effects of α₂M on interleukin‐1 (IL‐1)–induced cartilage catabolic enzymes were evaluated by Luminex assay and ELISA. In vivo effects on cartilage degeneration and matrix metalloproteinase 13 (MMP‐13) concentration were evaluated in male rats (n = 120) randomized to 1 of 4 treatments: 1) anterior cruciate ligament transection (ACLT) and saline injections, 2) ACLT and 1 IU/kg injections of α₂M, 3) ACLT and 2 IU/kg injections of α₂M, or 4) sham operation and saline injections. Rats were administered intraarticular injections for 6 weeks. The concentration of MMP‐13 in SF lavage fluid was measured using ELISA. OA‐related gene expression was quantified by real‐time quantitative polymerase chain reaction. The extent of OA progression was graded by histologic examination.Results: In both normal subjects and OA patients, α₂M levels were lower in SF as compared to serum, and in OA patients, MMP‐13 levels were higher in SF than in serum. In vitro, α₂M inhibited the induction of MMP‐13 by IL‐1 in a dose‐dependent manner in human chondrocytes. In the rat model of ACLT OA, supplemental intraarticular injection of α₂M reduced the concentration of MMP‐13 in SF, had a favorable effect on OA‐related gene expression, and attenuated OA progression.Conclusion: The plasma protease inhibitor α₂M is not present in sufficient concentrations to inactivate the high concentrations of catabolic factors found in OA SF. Our findings suggest that supplemental intraarticular α₂M provides chondral protection in posttraumatic OA.