Rspo2, or R-spondin 2, is a secreted protein that functions as a regulator of multiple signaling pathways, most notably the Wnt signaling pathway. It plays crucial roles in embryonic development, tissue homeostasis, and has implications in various disease processes [1-10]. Rspo2 can interact with receptors like LGR4, LGR5, and LGR6, as well as transmembrane ligases RNF43 and ZNRF3, modulating signaling outputs [6].

In multiple disease models, Rspo2 has distinct effects. In breast cancer, Rspo2, along with RANKL, signals through LGR4 to regulate osteoclastic pre-metastatic niche formation and bone metastasis. Soluble LGR4 ECD protein, acting as a decoy receptor for Rspo2 and RANKL, alleviates bone metastasis in mouse models [1]. In tendon/ligament, Rspo2 is expressed in a distinct undifferentiated Prg4+ TSPC cluster and its overexpression suppresses ectopic ossification in a mouse Achilles tendon puncture model [2]. In rheumatoid arthritis, Rspo2 exacerbates the disease by targeting the aggressive phenotype of fibroblast-like synoviocytes and disrupting chondrocyte homeostasis via the Wnt/β-catenin pathway, and neutralization of Rspo2 alleviates experimental RA development in mice [3]. In ovarian cancer, Rspo2 promotes growth and metastasis through dual receptor-mediated FAK/Src signaling activation [4]. In acute myeloid leukemia, Rspo2 inhibits BMP signaling to promote self-renewal, and inhibiting Rspo2 prolongs survival in AML mouse xenograft models [5]. In nasopharyngeal carcinoma, silencing Rspo2 inhibits tumorigenesis via the ZNRF3/Hedgehog-Gli1 signal pathway [7]. In glioblastoma, the miR-497-5p-Rspo2 axis inhibits cell growth and metastasis by suppressing the Wnt/β-catenin signaling pathway [8].

In conclusion, Rspo2 is a key regulator in multiple biological processes and disease conditions. Gene-knockout and conditional-knockout mouse models have been instrumental in revealing its functions in cancer metastasis, bone-related diseases, and joint-related diseases. Understanding Rspo2's roles provides potential therapeutic targets for these diseases.