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.

Intervertebral disc degeneration is a major contributor to discogenic low back pain and is characterized by a pro-inflammatory and catabolic microenvironment within the nucleus pulposus. We previously showed that the phosphatase PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) is positively correlated with intervertebral disc degeneration and that its deficiency promoted nucleus pulposus cell survival and matrix homeostasis; however, its role in inflammatory signaling during intervertebral disc degeneration remained unknown. Here, we show that PHLPP1 functions as an upstream regulator of inflammatory and catabolic networks in the degenerating intervertebral disc. In aged mice, Phlpp1 deficiency attenuated spontaneous intervertebral disc degeneration and reduced expression of IL1B and IL6. Notably, severe age-associated degeneration and inflammation were observed primarily in male wildtype mice, where the protective effects of Phlpp1 deletion were most apparent. To define the underlying mechanisms in human disease, we performed transcriptomic profiling of degenerated human nucleus pulposus cells following siRNA-mediated PHLPP1 silencing. PHLPP1 depletion induced widespread transcriptional reprogramming characterized by suppression of inflammatory cytokines, chemokines, and matrix-degrading enzymes, while promoting expression of extracellular matrix-associated genes. Pathway enrichment and network analyses identified coordinated inhibition of cytokine–cytokine receptor interaction, TNF, IL17, chemokine, and NFKB signaling pathways, revealing PHLPP1 as a central node linking cytokine amplification, immune cell recruitment, and matrix degradation. These findings were validated by reduced expression of IL1A, IL1B, IL6, CXCL2, CCL20, and STAT1, alongside increased ACAN expression. Furthermore, PHLPP1 silencing attenuated IL1B-induced inflammatory activation and matrix suppression and reduced STAT1 phosphorylation after IL1B stimulation. Collectively, our findings identify PHLPP1 as a critical regulator coupling inflammatory amplification to matrix remodeling in degenerating intervertebral discs and nominate PHLPP1 inhibition as a potential disease-modifying therapeutic strategy for intervertebral disc degeneration.