Sfrp4, Secreted Frizzled Receptor Protein 4, is a decoy receptor for Wnt ligands, playing a crucial role in various biological processes. It is involved in the regulation of Wnt signaling pathways, which are essential for normal development, cell differentiation, and tissue homeostasis. Sfrp4 has significance in multiple biological systems, including the skeletal, reproductive, and cardiovascular systems, and its study using genetic models, like KO mouse models, has provided valuable insights into its functions [1-10].

In the skeletal system, Sfrp4 loss-of-function mutations cause Pyle disease, characterized by cortical bone thinning and increased fragility fractures despite increased trabecular bone density. On the endosteal surface, it represses non-canonical Wnt signaling to regulate endosteal resorption. In the periosteum, Sfrp4 is crucial for the expansion and differentiation of periosteal stem cell/progenitor cells. Sfrp4 deletion decreases the pool of Ctsk-lineage periosteal stem cells, impairs their multipotency, and hampers the periosteal response to bone injury [1,2].

In the ovary, Sfrp4-null female mice are hyperfertile due to decreased antral follicle atresia and enhanced ovulation rates. Sfrp4 promotes autophagy and blunts FSH responsiveness in ovarian granulosa cells through inhibition of AKT signaling. It also contributes to insulin-resistance-induced polycystic ovary syndrome by triggering ovarian granulosa cell hyperandrogenism and apoptosis through the nuclear β-catenin/IL-6 signaling axis [3,6,7].

In ApoE-deficient mice, overexpression of SFRP4 reduces atherosclerosis plaque formation [4]. In gastric cancer, elevated SFRP4 expression is linked to a poor prognosis and is associated with immune cell infiltration [5]. In endometrial carcinoma, PBX1 promotes SFRP4 transcription, which inhibits cell proliferation and epithelial-mesenchymal transition [8].

In conclusion, Sfrp4 is a key regulator in multiple biological processes. Studies using KO mouse models have revealed its important roles in bone development, female fertility, and disease conditions such as Pyle disease, polycystic ovary syndrome, atherosclerosis, and certain cancers. Understanding Sfrp4 functions provides potential therapeutic targets for these diseases.