SHP-2 deletion in CD4Cre expressing chondrocyte precursors leads to tumor development with wrist tropism

Due to redundancy with other tyrosine phosphatases, the ubiquitously expressed tyrosine phosphatase SHP-2 (encoded by Ptpn11) is not required for T cell development. However, Ptpn11 gene deletion driven by CD4 Cre recombinase leads to cartilage tumors in the wrist. Using a fate mapping system, we demonstrate that wrist tumor development correlates with increased frequency and numbers of non-hematopoietic lineage negative CD45 negative cells with a bone chondrocyte stromal cell precursor cell (BCSP) phenotype. Importantly, the BCSP subset has a history of CD4 expression and a marked wrist location tropism, explaining why the wrist is the main site of tumor development. Mechanistically, we found that in SHP-2 absence, SOX-9 is no longer regulated, leading to an uncontrolled proliferation of the BCSP subset. Altogether, these results identify a unique subset of chondrocyte precursors tightly regulated by SHP-2. These findings underscore the need for the development of methods to therapeutically target this subset of cells, which could potentially have an impact on treatment of SHP-2 dysfunction linked debilitating diseases.

Distinct roles of glutamine metabolism in benign and malignant cartilage tumors with IDH mutations

Enchondromas and chondrosarcomas are common cartilage neoplasms that are either benign or malignant respectively. The majority of these tumors harbor mutations in either IDH1 or IDH2. Glutamine metabolism has been implicated as a critical regulator of tumors with IDH mutations. Chondrocytes and chondrosarcomas with mutations in the IDH1 or IDH2 genes showed enhanced glutamine utilization in downstream metabolism. Using genetic and pharmacological approaches, we demonstrated that glutaminase-mediated glutamine metabolism played distinct roles in enchondromas and chondrosarcomas with IDH1 or IDH2 mutations. Deletion of glutaminase in chondrocytes with Idh1 mutation increased the number and size of enchondroma-like lesions. Pharmacological inhibition of glutaminase in chondrosarcoma xenografts reduced overall tumor burden. Glutamine affected cell differentiation and viability in these tumors differently through different downstream metabolites. During murine enchondroma-like lesion development, glutamine-derived α-ketoglutarate promoted hypertrophic chondrocyte differentiation and regulated chondrocyte proliferation. In human chondrosarcoma, glutamine-derived non-essential amino acids played an important role in preventing cell apoptosis. This study reveals that glutamine metabolism can play distinct roles in benign and malignant cartilage tumors sharing the same genetic mutations. Inhibiting GLS may provide a therapeutic approach to suppress chondrosarcoma tumor growth.

Ollier disease: multiple enchondromatosis: case report and review of literature

Multiple enchondromatosis is a rare disease in which cartilage tumors appear at the level of the skeleton. The incidence is unknown due to the very few cases reported in world literature. We presented the case of a patient at the plastic surgery department at General hospital Dr. Ruben Leñero, otherwise healthy, referring first clinical manifestations at childhood with an increase in volume and deformity at the second and third fingers of the left hand.

SHP-2 deletion in CD4+ chondrocyte precursors leads to tumor development with wrist tropism

Due to redundancy with other tyrosine phosphatases, the ubiquitously expressed tyrosine phosphatase SHP-2 (encoded by Ptpn11) is not required for T cell development. However, Ptpn11 gene deletion driven by CD4 Cre recombinase leads to cartilage tumors in the wrist. Using a fate mapping system, we demonstrate that wrist tumor development correlates with increased frequency and numbers of non-hematopoietic CD45 negative cells with a bone chondrocyte stromal cell precursor cell (BCSP) phenotype. Importantly, the BCSP subset has a history of CD4 expression and a marked wrist location tropism, explaining why the wrist is the main site of tumor development. Mechanistically, we found that in SHP-2 absence, SOX-9 is no longer regulated, leading to an uncontrolled proliferation of the BCSP subset. Altogether, these results identify a unique subset of chondrocyte precursors tightly regulated by SHP-2. These findings underscore the need for the development of methods to therapeutically target this subset of cells, which could potentially have an impact on treatment of SHP-2 dysfunction linked debilitating diseases.

Mutant IDH is sufficient to initiate enchondromatosis in mice

Enchondromas are benign cartilage tumors and precursors tomalignant chondrosarcomas. Somatic mutations in the isocitratedehydrogenase genes (IDH1 and IDH2) are present in the majorityof these tumor types. How these mutations cause enchondromasis unclear. Here, we identified the spectrum of IDH mutations inhuman enchondromas and chondrosarcomas and studied theireffects in mice. A broad range of mutations was identified, includingthe previously unreported IDH1-R132Q mutation. These mutationsharbored enzymatic activity to catalyze α-ketoglutarate toD-2-hydroxyglutarate (D-2HG). Mice expressing Idh1-R132Q in oneallele in cells expressing type 2 collagen showed a disorderedgrowth plate, with persistence of type X-expressing chondrocytes.Chondrocyte cell cultures from these animals or controls showedthat there was an increase in proliferation and expression of genescharacteristic of hypertrophic chondrocytes with expression ofIdh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutantknock-in mice (mutant allele expressed in chondrocytes) did notsurvive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutantconditional knock-in mice, in which Cre was induced by tamoxifenafter weaning, developed multiple enchondroma-like lesions.Taken together, these data show that mutant IDH or D-2HG causespersistence of chondrocytes, giving rise to rests of growth-platecells that persist in the bone as enchondromas.

“False Patellar Duplication” Originated from Synovial Osteochondromatosis in Knee Joint: A Rare Case Report

BACKGROUND: “False patellar duplication” is a situation where there are two pieces in the position of a knee-joint like patella. It can derive from cartilage tumors, soft tissue tumors, or gout tumors, or due to the heterotopic ossification, forming a sub patella in the knee joint. CASE REPORT: A woman, 57 years old, healthy history, she has hospitalized for right knee joint pain since 2 years. Diagnosis: the synovial osteochondromatosis of the right knee. We decided to conduct and arthroscopy and removal. After 18 months surgery, the patient knee joint is currently good, range of motion (ROM) (-10)°- 0°-160°, Lysholm Knee Scoring Scale 85/100 point. CONCLUSION: This is the second case in the world and the first case in Vietnam. This is an experience in the process of diagnosis, arthroscopic treatment and differentiation from the "double patellae" status.

Integrated molecular characterization of chondrosarcoma reveals critical determinants of disease progression

Chondrosarcomas are primary cancers of cartilaginous tissue with highly contrasting prognoses. These tumors are defined by recurrent mutations in the IDH genes and other genetic alterations including inactivation of CDKN2A and COL2A1; however, these have no clinical value. Here we use multi-omics molecular profiles from a series of cartilage tumors and find an mRNA classification that identifies two subtypes of chondrosarcomas defined by a balance in tumor differentiation and cell cycle activation. The microRNA classification reveals the importance of the loss of expression of the 14q32 locus in defining the level of malignancy. Finally, DNA methylation is associated with IDH mutations. We can use the multi-omics classifications to predict outcome. We propose an mRNA-only classifier to reproduce the integrated multi-omics classification, and its application to relapsed tumor samples shows the progressive nature of the classification. Thus, it may be possible to use mRNA-based signatures to detect patients with high-risk chondrosarcomas.