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. Using genetic and pharmacological approaches, we demonstrated that
glutaminase-mediated
glutamine metabolism played distinct roles in
enchondromas and
chondrosarcomas with IDH1 or IDH2 mutations.
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. Deletion of
glutaminase in chondrocytes with Idh1 mutation increased the number and size of
enchondroma-like lesions. In contrast, pharmacological inhibition of
glutaminase in
chondrosarcoma xenografts reduced overall
tumor burden partially because
glutamine-derived non-
essential amino acids played an important role in preventing cell apoptosis. This study demonstrates that
glutamine metabolism plays different roles in
tumor initiation and
cancer maintenance. Supplementation of α-ketoglutarate and inhibiting GLS may provide a therapeutic approach to suppress
enchondroma and
chondrosarcoma tumor growth, respectively. © 2022 The Authors. Journal of Bone and
Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and
Mineral Research (ASBMR).