{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nF-spondin is an extracellular matrix protein that plays a multifaceted role across diverse biological systems. In the skeletal system, it acts as a negative regulator of bone mass by modulating key signaling pathways; deletion of its gene (Spon1) in mice led to increased bone deposition and turnover, likely through a systemic and local reduction in transforming growth factor‐β levels and a concomitant upregulation of bone morphogenetic protein (BMP) signaling (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "]).\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn vascular smooth muscle cells, F-spondin is upregulated in response to lipopolysaccharide through TLR4-mediated activation of the PI3K/Akt pathway. This increase in F-spondin drives the phosphorylation of CREB, thereby enhancing IL-6 production as well as promoting cell migration, proliferation, and MMP9 expression—mechanisms that underpin its role in the progression of atherosclerosis (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "]).\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWithin the framework of embryonic cartilage development, F-spondin expression localizes to hypertrophic and calcified zones of the growth plate, where it facilitates chondrocyte terminal differentiation and mineral deposition. Its promotive effects on the expression of differentiation markers such as alkaline phosphatase and matrix metalloproteinase-13 are, at least in part, mediated through interactions involving its thrombospondin domain and TGF‐β–dependent pathways (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "]).\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the central nervous system, F-spondin has an unexpected yet critical role in regulating circadian rhythms. Loss of F-spondin disrupts the proper positioning of vasoactive intestinal peptide–expressing neurons in the suprachiasmatic nucleus, ultimately impairing the intrinsic rhythmicity that is essential for normal circadian behavior (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "]).\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nF-spondin also exhibits neuroprotective functions in the context of Alzheimer’s disease. By binding to the amyloid precursor protein at the BACE1 binding site, it interferes with the amyloidogenic processing that leads to amyloid-β accumulation. This interaction underlies its ability to reduce amyloid burden and ameliorate cognitive deficits, pointing to a potential therapeutic strategy in AD (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "]).\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the immune system, F-spondin contributes to macrophage function by mediating the production of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) following CpG-B oligodeoxynucleotide stimulation. This F-spondin–dependent induction of IL-1Ra promotes macrophage migration and proliferation through downregulation of cell cycle inhibitors, thus influencing immune cell dynamics (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "]).\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, in reproductive biology, F-spondin is implicated in regulating embryo implantation. Elevated levels of uterine F-spondin induced by estrogen metabolites such as 2-methoxyoestradiol impair embryo implantation, an effect that can be blocked by neutralizing F-spondin activity. This finding links F-spondin’s extracellular matrix functions to the regulation of implantation dynamics (["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "]).\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Glyn D Palmer, Mukundan G Attur, Qing Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "F-spondin deficient mice have a high bone mass phenotype."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0098388"}], "href": "https://doi.org/10.1371/journal.pone.0098388"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24875054"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24875054"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Guan-Lin Lee, Jing-Yiing Wu, Chang-Ching Yeh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TLR4 induces CREB-mediated IL-6 production via upregulation of F-spondin to promote vascular smooth muscle cell migration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2016.04.040"}], "href": "https://doi.org/10.1016/j.bbrc.2016.04.040"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27091427"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27091427"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Glyn D Palmer, Alejandro H Piton, Lwin Mon Thant, et al. "}, {"type": "b", "children": [{"type": "t", "text": "F-spondin regulates chondrocyte terminal differentiation and endochondral bone formation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Orthop Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jor.21130"}], "href": "https://doi.org/10.1002/jor.21130"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20839318"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20839318"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Gabriela L Carrillo, Jianmin Su, Aboozar Monavarfeshani, et al. "}, {"type": "b", "children": [{"type": "t", "text": "F-spondin Is Essential for Maintaining Circadian Rhythms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Neural Circuits (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fncir.2018.00013"}], "href": "https://doi.org/10.3389/fncir.2018.00013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29472844"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29472844"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Soo Yong Park, Joo Yeong Kang, Taehee Lee, et al. "}, {"type": "b", "children": [{"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "SPON1"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Can Reduce Amyloid Beta and Reverse Cognitive Impairment and Memory Dysfunction in Alzheimer's Disease Mouse Model."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cells (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/cells9051275"}], "href": "https://doi.org/10.3390/cells9051275"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32455709"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32455709"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Tai-An Chen, Chiao-Chun Liao, Yung-Chih Cheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Stimulation of Proliferation and Migration of Mouse Macrophages by Type B CpG-ODNs Is F-Spondin and IL-1Ra Dependent."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0128926"}], "href": "https://doi.org/10.1371/journal.pone.0128926"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26042735"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26042735"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Emanuel Guajardo-Correa, Denisse Mena-Silva, Patricia Diaz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "2-Methoxyoestradiol impairs mouse embryo implantation via F-spondin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Reprod Fertil Dev (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1071/RD18114"}], "href": "https://doi.org/10.1071/RD18114"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30449298"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30449298"}]}]}]}