A 55-year-old man with squamous cell carcinoma of the lung develops hypercalcemia despite no bone metastases on imaging. Serum PTH is suppressed but PTHrP is markedly elevated. Which downstream signaling pathway does PTHrP primarily activate to cause osteoclast-mediated bone resorption in this paraneoplastic setting?

• A Wnt/β-catenin pathway in osteoclast precursors
• B RANK-RANKL pathway via cAMP-PKA signaling in osteoblasts ✓
• C JAK-STAT3 pathway in osteoclasts directly
• D NF-κB pathway via direct binding to osteoclast RANK

Explanation

PTHrP binds PTH/PTHrP receptor-1 on osteoblasts, activating adenylyl cyclase and raising cAMP, which triggers PKA. Activated osteoblasts upregulate RANKL and suppress OPG, resulting in RANK-RANKL driven osteoclastogenesis and hypercalcemia of malignancy. The Wnt pathway actually promotes bone formation; JAK-STAT and direct NF-κB mechanisms are not the primary route for PTHrP-mediated hypercalcemia.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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