RSPO2 (R-spondin 2) is a secreted Wnt pathway activator that functions as a ligand for LGR4-6 receptors, triggering canonical Wnt/β-catenin signaling 12. Uniquely, RSPO2 also acts independently of LGR4-6 as a direct antagonistic ligand to the E3 ubiquitin ligases RNF43 and ZNRF3, which serve as master regulators of limb specification during embryonic development 3. Beyond development, RSPO2 has emerged as a pathogenic mediator in multiple disease contexts. In osteoarthritis, synovial M1-polarized macrophages and Prg4+ fibroblasts secrete RSPO2, which activates β-catenin signaling in chondrocytes to exacerbate cartilage damage 12. Similarly, in rheumatoid arthritis, elevated RSPO2 expression promotes fibroblast-like synoviocyte aggression and disrupts chondrocyte homeostasis via Wnt/β-catenin activation 4. In cancer, RSPO2 upregulation enhances gastric cancer cell invasion and migration through LGR5-dependent Wnt signaling 5, while in breast cancer bone metastasis, RSPO2-LGR4 signaling on osteoclast precursors facilitates premetastatic niche formation 6. These findings position RSPO2 neutralization and Wnt pathway inhibition as potential therapeutic strategies for arthritis and cancer-related pathologies.