FRZB (frizzled-related protein) is a soluble Wnt signaling modulator that functions as a competitive antagonist of Wnt ligands by direct binding 1. Primarily, FRZB regulates skeletal development and chondrocyte maturation through negative regulation of canonical Wnt signaling, thereby suppressing cell growth and proliferation in bone and cartilage tissues. The protein localizes to both cytoplasm and nuclear membranes 2, enabling its inhibitory effects on Wnt-dependent pathways. In osteoarthritis (OA), FRZB expression is progressively lost during cartilage degeneration; its absence correlates with increased hypertrophic marker expression and cartilage degradation, suggesting FRZB normally maintains cartilage homeostasis 3. Beyond skeletal pathology, FRZB acts as a mechanistic regulator in age-related macular degeneration through WNT signaling modulation 1 and participates in vascular smooth muscle cell osteogenic transformation during atherosclerosis progression 4. Additionally, FRZB is elevated in degenerating intervertebral discs and serves as a predictive biomarker for disc degeneration 5, while also being altered in Alzheimer's disease plasma as part of amyloid-associated protein networks 6. Notably, genetic variants in FRZB show limited association with OA susceptibility in large population studies 78, suggesting its primary relevance is through expression modulation rather than genetic variation.