Role of Cathepsin K in Bone Invasion of Pituitary Adenomas: A Dual Mechanism Involving Cell Proliferation and Osteoclastogenesis

Purpose: This study aimed to explore the regulation and mechanism of Cathepsin K (CTSK) in bone invasive pituitary adenomas (BIPAs). Experimental Design: A total of 1437 patients with pituitary adenomas were included and followed up. RNA sequencing, immunohistochemistry, and RT-PCR were used to analyze to detect CTSK expression. The impact of CTSK on cellular proliferation, bone matrix degradation, and osteoclasts differentiation was determined by gain/loss of function experiments in vitro and vivo. The exploration of signaling pathway was determined by molecular biology experiments. Results: Here, we reported a significant fraction (~10%) of pituitary adenoma patients developed bone invasion. Bone invasion was correleted with tumor recurrence. Shorter recurrence free survival was found in BIPA patients. CTSK expression was increased in BIPA patients and strongly associated with worse prognosis. Increased CTSK expression promoted pituitary adenoma cell proliferation via activation of mammalian target of rapamycin (mTOR) signaling pathway and bone invasion via increasing osteoclast differentiation in vitro and in vivo. CTSK inhibitor (odanacatib) could inhibit pituitary adenoma cell proliferation and bone invasion in vitro and in vivo. CTSK promoted osteoclast differentiation by promoting the RANKL expression of MC3T3-E1 cells through interaction with TLR4. Conclusion: CTSK may become a novel predictive biomarker and potential therapeutic target for BIPAs.