The Role of GPR39 in Regulating Osteoblast Function, Bone Matrix Quality, and Gender‐Specific Bone Homeostasis

GPR39, a zinc-sensing receptor, is essential for bone homeostasis in male mice through regulation of osteoblast function and matrix composition. This study examined the effects of GPR39 deficiency in female mice using both global and osteoblast lineage-specific GPR39 knockout models (Gpr39^Ob-/Ob-). In vivo, GPR39-deficient female mice exhibited reduced bone mass, increased mineralization rates, and significantly lower and more variable serum levels of pro-collagen type I N-propeptide (PINP), indicating impaired collagen synthesis and matrix remodeling. OVX models further demonstrated that GPR39 deficiency exacerbates estrogen-deficiency-induced bone loss, highlighting its protective role in postmenopausal-like states. Osteoblast lineage-specific GPR39 deletion replicated the skeletal abnormalities observed in global knockouts, revealing that GPR39 activity in the osteoblast lineage is indispensable for proper collagen deposition and mineralization. Western blot analysis of Gpr39^Ob-/Ob- osteoblasts confirmed reduced extracellular collagen levels, while quantitative mRNA analysis of Col1a2 revealed zinc signaling through GPR39 as a key regulator of collagen production. Zinc-induced Col1a2 expression, dependent on GPR39 and mediated via Gα_q signaling, was abolished in GPR39-deficient osteoblasts. These findings provide insights into how zinc signaling via GPR39 regulates osteoblast function and collagen synthesis, emphasizing its role in maintaining matrix composition. Targeting GPR39 may offer novel therapeutic strategies for osteoporosis and other bone disorders characterized by impaired matrix remodeling.