{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ANKH is a multiple‐pass transmembrane protein that plays a central role in controlling extracellular mineralization by regulating the levels of key metabolites, most notably inorganic pyrophosphate (PPi) and citrate. In several studies, ANKH has been shown to facilitate the cellular release of ATP – which is rapidly converted into PPi by extracellular enzymes – thereby contributing to systemic PPi homeostasis that normally prevents ectopic calcification in soft tissues and joints."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In articular cartilage and bone, mutations in ANKH are associated with markedly divergent human skeletal disorders. For example, missense and small insertion/deletion mutations can lead to autosomal‐dominant forms of chondrocalcinosis, in which altered (often increased) ANKH activity results in abnormal PPi transport and the deposition of calcium pyrophosphate crystals"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", or to disorders such as craniometaphyseal dysplasia where loss of PPi transport function contributes to excessive, although hypomineralized, bone formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, ANKH functions are not limited to PPi regulation. Recent work indicates that ANKH can also mediate the export of other molecules such as citrate, which is an important component of the bone matrix and contributes to the mechanical properties of bone."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In addition, altered ANKH expression has been implicated in vascular calcification. Inflammatory mediators, via NF-κB and downstream molecules, suppress ANKH levels in vascular smooth muscle cells thereby reducing PPi efflux and promoting pathological calcification."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n ANKH also participates in the finely tuned regulation of bone remodeling and geometry. Genetic association studies point to polymorphisms in the ANKH gene contributing to variations in bone size, shape, and markers of bone turnover."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In addition, mechanotransduction and local microenvironmental cues, including miRNA‐mediated regulation, can modulate ANKH expression in chondrocytes, thereby influencing calcification processes in tissues such as the cartilage endplate."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings demonstrate that ANKH is a multifunctional protein essential for maintaining extracellular PPi and citrate balance. Its proper function is critical for preventing unwanted mineralization, whereas mutations or dysregulation of ANKH contribute to a spectrum of calcification disorders affecting the joints, vasculature, and skeleton (1,2,3,4,5,6,7,8,9).\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Robert S Jansen, Suzanne Duijst, Sunny Mahakena, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arterioscler Thromb Vasc Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/ATVBAHA.114.304017"}], "href": "https://doi.org/10.1161/ATVBAHA.114.304017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24969777"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24969777"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Adrian Pendleton, Michelle D Johnson, Anne Hughes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in ANKH cause chondrocalcinosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/343054"}], "href": "https://doi.org/10.1086/343054"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12297987"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12297987"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Charlene J Williams, Yun Zhang, Andrew Timms, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autosomal dominant familial calcium pyrophosphate dihydrate deposition disease is caused by mutation in the transmembrane protein ANKH."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/343053"}], "href": "https://doi.org/10.1086/343053"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12297989"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12297989"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Kyle A Gurley, Richard J Reimer, David M Kingsley "}, {"type": "b", "children": [{"type": "t", "text": "Biochemical and genetic analysis of ANK in arthritis and bone disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/509881"}], "href": "https://doi.org/10.1086/509881"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17186460"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17186460"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Flora Szeri, Stefan Lundkvist, Sylvia Donnelly, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The membrane protein ANKH is crucial for bone mechanical performance by mediating cellular export of citrate and ATP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1008884"}], "href": "https://doi.org/10.1371/journal.pgen.1008884"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32639996"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32639996"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Gexin Zhao, Ming-Jiang Xu, Ming-Ming Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activation of nuclear factor-kappa B accelerates vascular calcification by inhibiting ankylosis protein homolog expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Kidney Int (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ki.2012.40"}], "href": "https://doi.org/10.1038/ki.2012.40"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22437419"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22437419"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Ida Malkin, Stefan Dahm, Anita Suk, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of ANKH gene polymorphisms with radiographic hand bone size and geometry in a Chuvasha population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Bone (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bone.2004.09.002"}], "href": "https://doi.org/10.1016/j.bone.2004.09.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15780964"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15780964"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Yulia Vistoropsky, Michal Keter, Ida Malkin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Contribution of the putative genetic factors and ANKH gene polymorphisms to variation of circulating calciotropic molecules, PTH and BGP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddm071"}], "href": "https://doi.org/10.1093/hmg/ddm071"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17403715"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17403715"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Ming-Han Liu, Chao Sun, Yuan Yao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Matrix stiffness promotes cartilage endplate chondrocyte calcification in disc degeneration via miR-20a targeting ANKH expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep25401"}], "href": "https://doi.org/10.1038/srep25401"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27142968"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27142968"}]}]}]}