Role of Cathepsin K in bone invasion of pituitary adenomas: A dual mechanism involving cell proliferation and osteoclastogenesis.

Summary

In a 1,437-patient cohort with translational experiments, CTSK was upregulated in bone-invasive pituitary adenomas, predicted worse recurrence-free survival, and drove tumor proliferation via mTOR and osteoclastogenesis via TLR4–RANKL. Pharmacologic inhibition with odanacatib curtailed proliferation and bone invasion in vitro and in vivo, nominating CTSK as a biomarker and therapeutic target.

Key Findings

• Approximately 10% of pituitary adenomas exhibited bone invasion, which correlated with shorter recurrence-free survival.
• CTSK expression was increased in bone-invasive tumors and associated with worse prognosis.
• CTSK drove proliferation via mTOR activation and promoted osteoclastogenesis by inducing RANKL through TLR4; odanacatib inhibited these phenotypes in vitro and in vivo.

Clinical Implications

CTSK expression could be used to stratify pituitary adenoma patients for bone invasion risk and recurrence. CTSK inhibition (e.g., odanacatib) warrants clinical evaluation as an adjuvant therapy to limit invasion.

Limitations

• Cohort appears retrospective with potential selection and measurement biases
• No human interventional trial to confirm clinical efficacy of CTSK inhibition
• Generalizability beyond study population requires validation

Future Directions

Prospective validation of CTSK as a prognostic biomarker, and early-phase clinical trials of CTSK inhibitors in invasive pituitary adenomas; mechanistic dissection of TLR4–mTOR crosstalk.