In multiple myeloma, osteolytic bone disease is a major cause of morbidity. Which molecular pathway is primarily responsible for the uncoupling of bone remodeling in favor of osteoclast-mediated bone resorption?

• A Activating mutations in the Wnt signaling pathway
• B Constitutive activation of the JAK-STAT pathway in osteoblasts
• C Autocrine IL-6 production by osteoclasts
• D Overexpression of RANKL by marrow stromal cells with decreased osteoprotegerin (OPG) ✓

Explanation

Myeloma cells adhere to marrow stromal cells, which upregulate RANKL and downregulate its decoy receptor OPG. Elevated RANKL/OPG ratio drives osteoclast activation and bone resorption. Bisphosphonates and denosumab (anti-RANKL) are used therapeutically. JAK-STAT drives MPNs; IL-6 is a myeloma growth factor but acts indirectly; Wnt pathway suppression (not activation) occurs in myeloma bone disease via DKK1.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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