{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nCollagen VI is an essential extracellular matrix protein complex whose heterotrimeric assembly includes the α3 chain (COL6A3), from which the bioactive peptide endotrophin is cleaved. Novel collagen VI chains that structurally resemble the COL6A3 chain have been identified and may substitute for it in basement membranes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In vivo studies using Col6a3 mutant mice have demonstrated that loss of functional COL6A3 results in subtle musculoskeletal defects, underscoring its role in tissue homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, overexpression of COL6A3 in fibroblasts disrupts normal contact inhibition by altering key growth regulatory pathways like Hippo and Wnt signaling, thereby promoting three‐dimensional cell growth and potentially contributing to tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn adipose tissue, proteolytic cleavage of COL6A3 produces endotrophin, which acts as a potent co‐stimulator of pathological processes. In experimental models, adipocyte‐specific overexpression of endotrophin under high‐fat diet conditions triggers fibrosis and inflammation that lead to insulin resistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Further mechanistic studies have shown that endotrophin suppresses lipolytic signals and alters lipid handling at the cellular level, resulting in adipocyte hypertrophy and hyperplasia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe detrimental effects of endotrophin are not confined to adipose tissue. In the liver, high local levels of endotrophin induce JNK‐dependent apoptosis, activate nonparenchymal cell populations, and promote a proinflammatory, profibrotic milieu that is associated with non‐alcoholic steatohepatitis and hepatocellular carcinoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Additionally, in articular cartilage, interactions between type VI collagen and membrane receptors such as NG2 influence extracellular matrix stability and, when disrupted, contribute to the degeneration observed in temporomandibular joint osteoarthritis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging data also point to a regulatory role for intronic microRNAs in the control of host gene expression. MIR6863, an intronic miRNA genetically linked to COL6A3, is postulated to modulate the expression and function of its host gene and its cleavage product endotrophin. Given the established involvement of COL6A3/endotrophin in fibrosis, metabolic dysfunction, tumor progression, and extracellular matrix remodeling, MIR6863 may serve as an important fine‐tuner in these pathological processes, including cardiovascular disease where this genomic linkage has been highlighted."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sudheer Kumar Gara, Paolo Grumati, Anna Urciuolo, et al. 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