{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTHBS4 plays an important role in the nervous system where it is expressed by neurons and accumulates in synapse‐rich regions such as the neuromuscular junction. Functional studies have shown that THBS4 promotes neurite outgrowth and appears to enhance presynaptic excitatory input—features that may contribute to neuropathic pain states as well as to the unique synaptic organization and cognitive capabilities observed in the human brain."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its neural functions, THBS4 serves as a critical extracellular matrix scaffold that influences musculoskeletal development. Distinctive Ca²⁺‐binding properties govern its structural interactions and stability, and experimental models demonstrate that THBS4 is essential for proper muscle attachment and ECM assembly at myotendinous junctions. Its interactions with other matrix components support collagen fibrillogenesis, modulate cartilage remodeling (as seen in osteoarthritis) and contribute to bone formation during endochondral ossification, while altered THBS4 expression has also been implicated in tendinopathy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant expression and dysregulation of THBS4 are emerging as common features in various human cancers. Studies have documented its overexpression in diffuse‐type gastric adenocarcinomas, as well as in colorectal, breast, prostate, hepatocellular, and bladder cancers. In these diverse tumor settings, THBS4 appears to promote disease progression by enhancing cell migration, invasion, and epithelial–mesenchymal transition, in part through interactions with integrins and activation of signaling cascades such as FAK/PI3K/AKT and MAPK. In some cancers, noncoding RNAs modulate THBS4 levels and its downstream oncogenic effects."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond development and cancer, THBS4 has been implicated in cardiovascular and inflammatory processes. A number of genetic and clinical studies suggest that variants in the THBS4 locus may modulate susceptibility to coronary heart disease, myocardial infarction, and peripheral arterial disease. Although the mechanistic underpinnings remain to be fully elucidated, THBS4 is thought to influence vascular inflammation, endothelial signaling and angiogenic responses that contribute to these disease states."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTHBS4 also contributes to tissue repair and remodeling. In cutaneous models, THBS4 is a downstream effector of TGF‐β signaling that fosters hypertrophic scar formation and enhances keratinocyte migration, thereby accelerating wound closure. These activities underscore the protein’s multifaceted role in regenerative responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, a distinct C‐terminal fragment of THBS4 has been shown to stimulate erythroid cell proliferation, suggesting that THBS4 may also participate in hematopoietic regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "S Arber, P Caroni "}, {"type": "b", "children": [{"type": "t", "text": "Thrombospondin-4, an extracellular matrix protein expressed in the developing and adult nervous system promotes neurite outgrowth."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (1995)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.131.4.1083"}], "href": "https://doi.org/10.1083/jcb.131.4.1083"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "7490284"}], "href": "https://pubmed.ncbi.nlm.nih.gov/7490284"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Mario Cáceres, Carolyn Suwyn, Marcelia Maddox, et al. 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