{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ADAMTS16 is a multifunctional, secreted metalloproteinase that participates in diverse physiological and pathological processes through extracellular matrix remodeling and proteolytic processing. Several studies have demonstrated that ADAMTS16 exhibits relatively low aggrecanase activity compared with other family members, suggesting that its catalytic efficiency may be modulated by its structural domains and post‐translational modifications."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the cardiovascular and renal systems, ADAMTS16 has emerged as a developmentally important protease. It is expressed in the kidney and is transcriptionally regulated by the Wilms tumor protein (Wt1), acting downstream to coordinate branching morphogenesis during urogenital development"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "; moreover, targeted disruption of Adamts16 in hypertensive rat models results in lower blood pressure and vascular remodeling, thereby linking this protease to blood pressure regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In reproductive tissues, ADAMTS16 is abundant in ovarian granulosa cells where its proteolytic activity—including cleavage of substrates such as alpha2‐macroglobulin—suggests a role in follicular maturation during the pre‐ovulatory phase."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In addition, genetic interactions between polymorphisms in ADAMTS16 and key reproductive genes have been linked with an increased risk for premature ovarian failure."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n ADAMTS16 is also implicated in tissue remodeling during repair and disease. In articular cartilage, its upregulated expression has been observed in osteoarthritis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", and studies in Dupuytren’s disease have correlated its elevated levels with disease recurrence"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", which supports a role for ADAMTS16 in remodeling of the extracellular matrix during fibrotic processes. In the context of wound healing, ADAMTS16 is part of a gene set expressed by activated myofibroblasts, indicating that it may contribute to extracellular matrix turnover during tissue repair."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In cancer, the functional role of ADAMTS16 appears to be context dependent. In colorectal carcinoma, promoter hypermethylation–and consequent loss of ADAMTS16 expression–correlates with enhanced tumor cell proliferation, implying a tumor‐suppressive function"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "; conversely, in esophageal squamous cell carcinoma, increased ADAMTS16 expression promotes cell growth and invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, post‐translational modification of ADAMTS16 is critical for its proper secretion and function. C‐mannosylation mediated by DPY19L enzymes facilitates the secretion of ADAMTS16, a process that is necessary for normal eye development, as evidenced by defects in optic fissure fusion when this modification fails."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, emerging evidence also points to associations between ADAMTS16 genetic variation and susceptibility to inflammatory and adaptive processes, as noted in canine anal furunculosis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "and high‐altitude adaptation in pigs"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", while insulin‐mediated regulation of ADAMTS16 in chondrosarcoma cells suggests an involvement in extracellular matrix turnover in response to metabolic cues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " Collectively, these findings underscore the pleiotropic roles of ADAMTS16 in modulating extracellular matrix dynamics, influencing organ development, vascular function, tissue repair, and disease progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "17"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Weilan Zeng, Chris Corcoran, Lisa A Collins-Racie, et al. 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