SFRP4 is a secreted Wnt antagonist that functions as a decoy receptor for Wnt ligands, modulating canonical and non-canonical Wnt signaling pathways 1. In bone, SFRP4 regulates periosteal stem cell expansion and endosteal resorption through non-canonical Wnt repression; loss-of-function mutations cause Pyle disease, characterized by cortical bone thinning and fracture susceptibility despite increased trabecular density 1. Beyond skeletal biology, SFRP4 marks distinct fibroblast subpopulations in fibrotic and inflammatory diseases. In systemic sclerosis, SFRP4-expressing fibroblasts correlate with progressive skin fibrosis and clinical severity 2. Similarly, SFRP4+ myofibroblasts are enriched in localized scleroderma skin lesions with inflammatory gene signatures 3, and hidradenitis suppurativa fibrosis 4. In reproductive biology, SFRP4+ stromal cells indicate impaired decidualization in preeclampsia, reflecting disrupted Wnt pathway signaling 5. In prostate cancer, SFRP4 expression in cancer-associated fibroblasts correlates with aggressiveness and extracellular matrix remodeling 6, with specific SFRP4 SNPs associated with increased cancer risk 7. SFRP4 also exhibits phosphaturic effects by inhibiting sodium-dependent phosphate uptake. Overall, SFRP4 serves as a critical Wnt pathway regulator with roles in bone homeostasis, fibrosis progression, and cancer biology.