{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T15:14:12Z","timestamp":1791818052248,"version":"4.3.4"},"reference-count":113,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2021,8,28]],"date-time":"2021-08-28T00:00:00Z","timestamp":1630108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["STO 824\/5-1"],"award-info":[{"award-number":["STO 824\/5-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Vitamin K and Vitamin K-dependent proteins (VKDPs) are best known for their pivotal role in blood coagulation. Of the 14 VKPDs identified in humans to date, 6 play also important roles in skeletal biology and disease. Thus, osteocalcin, also termed bone Gla-protein, is the most abundant non-collagenous protein in bone. Matrix Gla protein and Ucma\/GRP on the other hand are highly abundant in cartilage. Furthermore, periostin, protein S, and growth arrest specific 6 protein (GAS 6) are expressed in skeletal tissues. The roles for these VKDPs are diverse but include the control of calcification and turnover of bone and cartilage. Vitamin K plays an important role in osteoporosis and serum osteocalcin levels are recognized as a promising marker for osteoporosis. On the other hand, matrix Gla protein and Ucma\/GRP are associated with osteoarthritis. This review focuses on the roles of these three VKDPs, osteocalcin, matrix Gla protein and Ucma\/GRP, in skeletal development and disease but will also summarize the roles the other skeletal VKDPs (periostin, protein S and GAS6) in skeletal biology.<\/jats:p>","DOI":"10.3390\/ijms22179328","type":"journal-article","created":{"date-parts":[[2021,8,29]],"date-time":"2021-08-29T21:45:16Z","timestamp":1630273516000},"page":"9328","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Vitamin K-Dependent Proteins in Skeletal Development and Disease"],"prefix":"10.3390","volume":"22","author":[{"given":"Michael","family":"Stock","sequence":"first","affiliation":[{"name":"Department of Internal Medicine 3, Friedrich Alexander University Erlangen-N\u00fcrnberg and Universit\u00e4tsklinium Erlangen, 91054 Erlangen, Germany"},{"name":"Zentrum f\u00fcr Immuntherapie, Friedrich Alexander University Erlangen-N\u00fcrnberg and Universit\u00e4tsklinikum Erlangen, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Schett","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine 3, Friedrich Alexander University Erlangen-N\u00fcrnberg and Universit\u00e4tsklinium Erlangen, 91054 Erlangen, Germany"},{"name":"Zentrum f\u00fcr Immuntherapie, Friedrich Alexander University Erlangen-N\u00fcrnberg and Universit\u00e4tsklinikum Erlangen, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1042\/bj0291273","article-title":"The antihaemorrhagic vitamin of the chick","volume":"29","author":"Dam","year":"1935","journal-title":"Biochem. J."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Azuma, K., and Inoue, S. (2019). Multiple Modes of Vitamin K Actions in Aging-Related Musculoskeletal Disorders. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20112844"},{"key":"ref_3","first-page":"129","article-title":"Apoptosis-inducing activity of vitamin C and vitamin K","volume":"46","author":"Sakagami","year":"2000","journal-title":"Cell Mol. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s007740170021","article-title":"Role of K vitamins in the regulation of tissue calcification","volume":"19","author":"Vermeer","year":"2001","journal-title":"J. Bone Miner. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"296721","DOI":"10.1155\/2015\/296721","article-title":"Vitamin K1 exerts antiproliferative effects and induces apoptosis in three differently graded human colon cancer cell lines","volume":"2015","author":"Orlando","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6254836","DOI":"10.1155\/2017\/6254836","article-title":"Vitamins K1 and K2: The Emerging Group of Vitamins Required for Human Health","volume":"2017","author":"Schwalfenberg","year":"2017","journal-title":"J. Nutr. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1007\/s13668-016-0162-x","article-title":"The Role of Vitamin K in Chronic Aging Diseases: Inflammation, Cardiovascular Disease, and Osteoarthritis","volume":"5","author":"Harshman","year":"2016","journal-title":"Curr. Nutr. Rep."},{"key":"ref_8","first-page":"8926","article-title":"Research progress on the anticancer effects of vitamin K2","volume":"15","author":"Xv","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3370","DOI":"10.1016\/j.clnu.2020.11.009","article-title":"Vitamin K intake and breast cancer incidence and death: Results from a prospective cohort study","volume":"40","author":"Wang","year":"2021","journal-title":"Clin. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S0022-3476(75)80986-3","article-title":"Congenital malformations associated with the administration of oral anticoagulants during pregnancy","volume":"86","author":"Pettifor","year":"1975","journal-title":"J. Pediatr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7734","DOI":"10.1073\/pnas.79.24.7734","article-title":"Excessive mineralization with growth plate closure in rats on chronic warfarin treatment","volume":"79","author":"Price","year":"1982","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1002\/jbmr.5650100221","article-title":"The matrix Gla protein gene is a marker of the chondrogenesis cell lineage during mouse development","volume":"10","author":"Luo","year":"1995","journal-title":"J. Bone Miner. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1152\/physrev.1989.69.3.990","article-title":"Osteocalcin and matrix Gla protein: Vitamin K-dependent proteins in bone","volume":"69","author":"Hauschka","year":"1989","journal-title":"Physiol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1083\/jcb.147.5.1097","article-title":"Matrix GLA protein is a developmental regulator of chondrocyte mineralization and, when constitutively expressed, blocks endochondral and intramembranous ossification in the limb","volume":"147","author":"Yagami","year":"1999","journal-title":"J. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/382448a0","article-title":"Increased bone formation in osteocalcin-deficient mice","volume":"382","author":"Ducy","year":"1996","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/386078a0","article-title":"Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein","volume":"386","author":"Luo","year":"1997","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4629383","DOI":"10.1155\/2018\/4629383","article-title":"Vitamin K and Bone Metabolism: A Review of the Latest Evidence in Preclinical Studies","volume":"2018","author":"Akbari","year":"2018","journal-title":"BioMed Res. Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1007\/s12020-014-0401-0","article-title":"A four-season molecule: Osteocalcin. Updates in its physiological roles","volume":"48","author":"Lombardi","year":"2015","journal-title":"Endocrine"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"16927","DOI":"10.1074\/jbc.M600896200","article-title":"Steroid and xenobiotic receptor SXR mediates vitamin K2-activated transcription of extracellular matrix-related genes and collagen accumulation in osteoblastic cells","volume":"281","author":"Ichikawa","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1677\/JOE-10-0208","article-title":"Pregnane X receptor knockout mice display osteopenia with reduced bone formation and enhanced bone resorption","volume":"207","author":"Azuma","year":"2010","journal-title":"J. Endocrinol."},{"key":"ref_21","first-page":"3","article-title":"Vitamin K2 stimulates osteoblastogenesis and suppresses osteoclastogenesis by suppressing NF-kappaB activation","volume":"27","author":"Yamaguchi","year":"2011","journal-title":"Int. J. Mol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7082","DOI":"10.1074\/jbc.M702792200","article-title":"Ucma, a novel secreted cartilage-specific protein with implications in osteogenesis","volume":"283","author":"Dietz","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.matbio.2007.07.004","article-title":"Ucma\u2014A novel secreted factor represents a highly specific marker for distal chondrocytes","volume":"27","author":"Tagariello","year":"2008","journal-title":"Matrix Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"36655","DOI":"10.1074\/jbc.M802761200","article-title":"Gla-rich Protein (GRP), A New Vitamin K-dependent Protein Identified from Sturgeon Cartilage and Highly Conserved in Vertebrates","volume":"283","author":"Viegas","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.matbio.2011.07.002","article-title":"Ucmaa (Grp-2) is required for zebrafish skeletal development. Evidence for a functional role of its glutamate gamma-carboxylation","volume":"30","author":"Neacsu","year":"2011","journal-title":"Matrix Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.bone.2011.11.017","article-title":"Ucma is not necessary for normal development of the mouse skeleton","volume":"50","author":"Eitzinger","year":"2012","journal-title":"Bone"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/s13075-018-1583-2","article-title":"Upper zone of growth plate and cartilage matrix associated protein protects cartilage during inflammatory arthritis","volume":"20","author":"Seuffert","year":"2018","journal-title":"Arthritis Res. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1002\/art.40042","article-title":"A Dual Role of Upper Zone of Growth Plate and Cartilage Matrix-Associated Protein in Human and Mouse Osteoarthritic Cartilage: Inhibition of Aggrecanases and Promotion of Bone Turnover","volume":"69","author":"Stock","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/stem.160229","article-title":"Tyro 3 receptor tyrosine kinase and its ligand, Gas6, stimulate the function of osteoclasts","volume":"16","author":"Nakamura","year":"1998","journal-title":"Stem Cells"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17991","DOI":"10.1074\/jbc.M708029200","article-title":"Periostin, a member of a novel family of vitamin K-dependent proteins, is expressed by mesenchymal stromal cells","volume":"283","author":"Coutu","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11131","DOI":"10.1128\/MCB.25.24.11131-11144.2005","article-title":"Periostin null mice exhibit dwarfism, incisor enamel defects, and an early-onset periodontal disease-like phenotype","volume":"25","author":"Rios","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Chijimatsu, R., Kunugiza, Y., Taniyama, Y., Nakamura, N., Tomita, T., and Yoshikawa, H. (2015). Expression and pathological effects of periostin in human osteoarthritis cartilage. BMC Musculoskelet. Disord., 16.","DOI":"10.1186\/s12891-015-0682-3"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Heo, S.C., Shin, W.C., Lee, M.J., Kim, B.R., Jang, I.H., Choi, E.J., Lee, J.S., and Kim, J.H. (2015). Periostin accelerates bone healing mediated by human mesenchymal stem cell-embedded hydroxyapatite\/tricalcium phosphate scaffold. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0116698"},{"key":"ref_34","first-page":"1599","article-title":"Protein-S, a vitamin K-dependent protein, is a bone matrix component synthesized and secreted by osteoblasts","volume":"130","author":"Maillard","year":"1992","journal-title":"Endocrinology"},{"key":"ref_35","first-page":"298","article-title":"Determination of phylloquinone and menaquinones in food. Effect of food matrix on circulating vitamin K concentrations","volume":"30","author":"Schurgers","year":"2000","journal-title":"Haemostasis"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6347","DOI":"10.1016\/S0021-9258(19)42259-X","article-title":"The mode of action of vitamin K. Identification of gamma-carboxyglutamic acid as a component of prothrombin","volume":"249","author":"Nelsestuen","year":"1974","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2730","DOI":"10.1073\/pnas.71.7.2730","article-title":"Vitamin K dependent modifications of glutamic acid residues in prothrombin","volume":"71","author":"Stenflo","year":"1974","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/nsmb.3338","article-title":"Warfarin and vitamin K compete for binding to Phe55 in human VKOR","volume":"24","author":"Czogalla","year":"2017","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1093\/ajcn\/69.1.74","article-title":"Vitamin K intake and hip fractures in women: A prospective study","volume":"69","author":"Feskanich","year":"1999","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1001\/archinte.159.15.1750","article-title":"Long-term use of oral anticoagulants and the risk of fracture","volume":"159","author":"Caraballo","year":"1999","journal-title":"Arch. Intern. Med."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Chin, K.Y. (2020). The Relationship between Vitamin K and Osteoarthritis: A Review of Current Evidence. Nutrients, 12.","DOI":"10.3390\/nu12051208"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1136\/annrheumdis-2020-219483","article-title":"Vitamin K antagonist anticoagulant usage is associated with increased incidence and progression of osteoarthritis","volume":"80","author":"Boer","year":"2021","journal-title":"Ann. Rheum. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/iub.41","article-title":"Vitamin K and rheumatoid arthritis","volume":"60","author":"Okamoto","year":"2008","journal-title":"IUBMB Life"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.3109\/s10165-012-0789-4","article-title":"Vitamin K2 administration is associated with decreased disease activity in patients with rheumatoid arthritis","volume":"23","author":"Ebina","year":"2013","journal-title":"Mod. Rheumatol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"108","DOI":"10.3164\/jcbn.13-25","article-title":"Vitamin K1 (phylloquinone) and K2 (menaquinone-4) supplementation improves bone formation in a high-fat diet-induced obese mice","volume":"53","author":"Kim","year":"2013","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7947","DOI":"10.1128\/MCB.00813-07","article-title":"Vitamin K induces osteoblast differentiation through pregnane X receptor-mediated transcriptional control of the Msx2 gene","volume":"27","author":"Igarashi","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1136\/annrheumdis-2014-205618","article-title":"Rsk2 controls synovial fibroblast hyperplasia and the course of arthritis","volume":"75","author":"Derer","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1056\/NEJMra1004965","article-title":"The pathogenesis of rheumatoid arthritis","volume":"365","author":"McInnes","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"40485","DOI":"10.1074\/jbc.M607704200","article-title":"Menadione-induced reactive oxygen species generation via redox cycling promotes apoptosis of murine pancreatic acinar cells","volume":"281","author":"Criddle","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nri2094","article-title":"Cytokines in the pathogenesis of rheumatoid arthritis","volume":"7","author":"McInnes","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"7376","DOI":"10.1074\/jbc.M007393200","article-title":"Mechanism of stimulation of osteoclastic bone resorption through Gas6\/Tyro 3, a receptor tyrosine kinase signaling, in mouse osteoclasts","volume":"276","author":"Katagiri","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/jbmr.5650070111","article-title":"The osteocalcin propeptide is not secreted in vivo or in vitro","volume":"7","author":"Gundberg","year":"1992","journal-title":"J. Bone Miner. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"8685","DOI":"10.1016\/S0021-9258(18)43554-5","article-title":"Isolation and sequence of the vitamin K-dependent protein from human bone. Undercarboxylation of the first glutamic acid residue","volume":"255","author":"Poser","year":"1980","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"51","DOI":"10.3109\/03008208909049995","article-title":"Gla-containing proteins of bone","volume":"21","author":"Price","year":"1989","journal-title":"Connect. Tissue Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1002\/ar.1092240208","article-title":"Osteocalcin-hydroxyapatite interaction in the extracellular organic matrix of bone","volume":"224","author":"Hauschka","year":"1989","journal-title":"Anat. Rec."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1038\/nature02079","article-title":"Bone recognition mechanism of porcine osteocalcin from crystal structure","volume":"425","author":"Hoang","year":"2003","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/S8756-3282(98)00092-1","article-title":"Fourier transform infrared microspectroscopic analysis of bones of osteocalcin-deficient mice provides insight into the function of osteocalcin","volume":"23","author":"Boskey","year":"1998","journal-title":"Bone"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1172\/JCI118428","article-title":"Bone mineralization in an osteogenesis imperfecta mouse model studied by small-angle X-ray scattering","volume":"97","author":"Fratzl","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/S0140-6736(84)92506-6","article-title":"Serum bone Gla-protein: A specific marker for bone formation in postmenopausal osteoporosis","volume":"1","author":"Brown","year":"1984","journal-title":"Lancet"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1002\/jbmr.5650061111","article-title":"Impairment of gamma carboxylation of circulating osteocalcin (bone gla protein) in elderly women","volume":"6","author":"Plantalech","year":"1991","journal-title":"J. Bone Miner. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S0009-8981(96)06418-2","article-title":"Osteocalcin detection in aging serum and whole blood: Stability of different osteocalcin fractions","volume":"256","author":"Knapen","year":"1996","journal-title":"Clin. Chim. Acta Int. J. Clin. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1172\/JCI116387","article-title":"Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women","volume":"91","author":"Szulc","year":"1993","journal-title":"J. Clin. Investig."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1093\/ajcn\/71.5.1201","article-title":"Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women","volume":"71","author":"Booth","year":"2000","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1093\/ajcn\/77.2.512","article-title":"Vitamin K intake and bone mineral density in women and men","volume":"77","author":"Booth","year":"2003","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1007\/s002230001108","article-title":"Chondrocyte differentiation in human osteoarthritis: Expression of osteocalcin in normal and osteoarthritic cartilage and bone","volume":"67","author":"Pullig","year":"2000","journal-title":"Calcif. Tissue Int."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1093\/rheumatology\/28.5.393","article-title":"Serum and synovial fluid osteocalcin (bone gla protein) levels in joint disease","volume":"28","author":"Campion","year":"1989","journal-title":"Br. J. Rheumatol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1002\/1529-0131(199805)41:5<891::AID-ART17>3.0.CO;2-X","article-title":"Osteoblast-like cells from human subchondral osteoarthritic bone demonstrate an altered phenotype in vitro: Possible role in subchondral bone sclerosis","volume":"41","author":"Hilal","year":"1998","journal-title":"Arthritis Rheum."},{"key":"ref_68","first-page":"756","article-title":"Relationship between serum undercarboxylated osteocalcin and hyaluronan levels in patients with bilateral knee osteoarthritis","volume":"29","author":"Naito","year":"2012","journal-title":"Int. J. Mol. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1111\/j.1749-6632.2002.tb04254.x","article-title":"Serum osteocalcin levels in premenopausal rheumatoid arthritis patients","volume":"966","author":"Seriolo","year":"2002","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_70","first-page":"333","article-title":"Molecular basis and clinical application of biological markers of bone turnover","volume":"17","author":"Calvo","year":"1996","journal-title":"Endocr. Rev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.joca.2011.01.022","article-title":"Osteoarthritis year 2010 in review: Pathomechanisms","volume":"19","year":"2011","journal-title":"Osteoarthr. Cartil."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.cell.2011.02.004","article-title":"Endocrine regulation of male fertility by the skeleton","volume":"144","author":"Oury","year":"2011","journal-title":"Cell"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.cell.2013.08.042","article-title":"Maternal and offspring pools of osteocalcin influence brain development and functions","volume":"155","author":"Oury","year":"2013","journal-title":"Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.cell.2007.05.047","article-title":"Endocrine regulation of energy metabolism by the skeleton","volume":"130","author":"Lee","year":"2007","journal-title":"Cell"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"5266","DOI":"10.1073\/pnas.0711119105","article-title":"Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice","volume":"105","author":"Ferron","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3374","DOI":"10.1073\/pnas.73.10.3374","article-title":"Primary structure of the gamma-carboxyglutamic acid-containing protein from bovine bone","volume":"73","author":"Price","year":"1976","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1073\/pnas.73.5.1447","article-title":"Characterization of a gamma-carboxyglutamic acid-containing protein from bone","volume":"73","author":"Price","year":"1976","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/S8756-3282(02)00821-9","article-title":"Matrix Gla protein binding to hydroxyapatite is dependent on the ionic environment: Calcium enhances binding affinity but phosphate and magnesium decrease affinity","volume":"31","author":"Roy","year":"2002","journal-title":"Bone"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1083\/jcb.200402046","article-title":"Extracellular matrix mineralization is regulated locally; different roles of two gla-containing proteins","volume":"165","author":"Murshed","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1055\/s-0037-1614168","article-title":"Modulation of the binding of matrix Gla protein (MGP) to bone morphogenetic protein-2 (BMP-2)","volume":"84","author":"Wallin","year":"2000","journal-title":"Thromb. Haemost."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1016\/j.joca.2010.05.013","article-title":"Biosynthesis of the vitamin K-dependent matrix Gla protein (MGP) in chondrocytes: A fetuin-MGP protein complex is assembled in vesicles shed from normal but not from osteoarthritic chondrocytes","volume":"18","author":"Wallin","year":"2010","journal-title":"Osteoarthr. Cartil."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1167\/iovs.05-1106","article-title":"Matrix GLA protein function in human trabecular meshwork cells: Inhibition of BMP2-induced calcification process","volume":"47","author":"Xue","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.3899\/jrheum.100985","article-title":"Matrix Gla protein polymorphism, but not concentrations, is associated with radiographic hand osteoarthritis","volume":"38","author":"Misra","year":"2011","journal-title":"J. Rheumatol."},{"key":"ref_84","first-page":"125","article-title":"Synovial and serum levels of uncarboxylated matrix Gla-protein (ucMGP) in patients with arthritis","volume":"50","author":"Silaghi","year":"2011","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.17219\/acem\/33824","article-title":"Attenuate Synovial Fluid Uncarboxylated Matrix Gla-Protein (ucMGP) Concentrations Are Linked with Radiographic Progression in Knee Psteoarthritis","volume":"24","author":"Bing","year":"2015","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1161\/HYPERTENSIONAHA.119.12412","article-title":"Vitamin K-Dependent Matrix Gla Protein as Multifaceted Protector of Vascular and Tissue Integrity","volume":"73","author":"Wei","year":"2019","journal-title":"Hypertension"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"891","DOI":"10.3389\/fendo.2019.00891","article-title":"Matrix Gla Protein Promotes the Bone Formation by Up-Regulating Wnt\/\u03b2-Catenin Signaling Pathway","volume":"10","author":"Zhang","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1016\/j.joca.2015.03.035","article-title":"Ucma, a direct transcriptional target of Runx2 and Osterix, promotes osteoblast differentiation and nodule formation","volume":"23","author":"Lee","year":"2015","journal-title":"Osteoarthr. Cartil."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.yexcr.2009.10.002","article-title":"Identification of four alternatively spliced transcripts of the Ucma\/GRP gene, encoding a new Gla-containing protein","volume":"316","author":"Tomavo","year":"2010","journal-title":"Exp. Cell Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1002\/mnfr.201300941","article-title":"Insights into the association of Gla-rich protein and osteoarthritis, novel splice variants and gamma-carboxylation status","volume":"58","author":"Rafael","year":"2014","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1074\/jbc.M308689200","article-title":"Identification of tyrosine sulfation in extracellular leucine-rich repeat proteins using mass spectrometry","volume":"279","author":"Onnerfjord","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/S0021-9258(17)35234-1","article-title":"Sulfation of Tyr1680 of human blood coagulation factor VIII is essential for the interaction of factor VIII with von Willebrand factor","volume":"266","author":"Leyte","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/j.bone.2012.06.028","article-title":"Genetic association study of UCMA\/GRP and OPTN genes (PDB6 locus) with Paget\u2019s disease of bone","volume":"51","author":"Michou","year":"2012","journal-title":"Bone"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"4961","DOI":"10.1038\/s41598-018-23353-y","article-title":"Ucma\/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling","volume":"8","author":"Willems","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1161\/ATVBAHA.117.310578","article-title":"Chronic Kidney Disease Circulating Calciprotein Particles and Extracellular Vesicles Promote Vascular Calcification: A Role for GRP (Gla-Rich Protein)","volume":"38","author":"Viegas","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.2353\/ajpath.2009.090474","article-title":"Gla-rich protein is a novel vitamin K-dependent protein present in serum that accumulates at sites of pathological calcifications","volume":"175","author":"Viegas","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Silva, A.P., Viegas, C.S., Mendes, F., Macedo, A., Guilherme, P., Tavares, N., Dias, C., Rato, F., Santos, N., and Faisca, M. (2020). Gla-Rich Protein (GRP) as an Early and Novel Marker of Vascular Calcification and Kidney Dysfunction in Diabetic Patients with CKD: A Pilot Cross-Sectional Study. J. Clin. Med., 9.","DOI":"10.3390\/jcm9030635"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1007\/s00018-015-2033-9","article-title":"Gla-rich protein is involved in the cross-talk between calcification and inflammation in osteoarthritis","volume":"73","author":"Cavaco","year":"2016","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1139\/cjpp-2020-0009","article-title":"In vivo protective effects of upper zone of growth plate and cartilage matrix associated protein against cartilage degeneration in a monosodium iodoacetate induced osteoarthritis model","volume":"98","author":"Okuyan","year":"2020","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1111\/1756-185X.13682","article-title":"Association of UCMA levels in serum and synovial fluid with severity of knee osteoarthritis","volume":"22","author":"Okuyan","year":"2019","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1359\/jbmr.1999.14.7.1239","article-title":"Identification and characterization of a novel protein, periostin, with restricted expression to periosteum and periodontal ligament and increased expression by transforming growth factor beta","volume":"14","author":"Horiuchi","year":"1999","journal-title":"J. Bone Miner. Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"35939","DOI":"10.1074\/jbc.M109.060335","article-title":"The matricellular protein periostin is required for sost inhibition and the anabolic response to mechanical loading and physical activity","volume":"284","author":"Bonnet","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1002\/jcb.21224","article-title":"Periostin regulates collagen fibrillogenesis and the biomechanical properties of connective tissues","volume":"101","author":"Norris","year":"2007","journal-title":"J. Cell. Biochem."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1016\/j.joca.2015.05.015","article-title":"Serum periostin is associated with prevalent knee osteoarthritis and disease incidence\/progression in women: The OFELY study","volume":"23","author":"Rousseau","year":"2015","journal-title":"Osteoarthr. Cartil."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.jbspin.2015.01.023","article-title":"Association of plasma and synovial fluid periostin with radiographic knee osteoarthritis: Cross-sectional study","volume":"82","author":"Honsawek","year":"2015","journal-title":"Jt. Bone Spine"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/s13075-021-02477-z","article-title":"Periostin loss-of-function protects mice from post-traumatic and age-related osteoarthritis","volume":"23","author":"Attur","year":"2021","journal-title":"Arthritis Res. Ther."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/0049-3848(90)90092-Q","article-title":"Bone mineral density and its association with inherited protein S deficiency","volume":"58","author":"Pan","year":"1990","journal-title":"Thromb. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/nature03417","article-title":"ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro","volume":"434","author":"Stanton","year":"2005","journal-title":"Nature"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1002\/art.22334","article-title":"Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5","volume":"56","author":"Song","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1038\/nature03369","article-title":"Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis","volume":"434","author":"Glasson","year":"2005","journal-title":"Nature"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1016\/j.joca.2015.02.778","article-title":"Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification","volume":"23","author":"Larkin","year":"2015","journal-title":"Osteoarthr. Cartil."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"10476","DOI":"10.1021\/jm501522n","article-title":"Identification of potent and selective hydantoin inhibitors of aggrecanase-1 and aggrecanase-2 that are efficacious in both chemical and surgical models of osteoarthritis","volume":"57","author":"Durham","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"19341","DOI":"10.1074\/jbc.C112.350785","article-title":"Novel role of ADAMTS-5 protein in proteoglycan turnover and lipoprotein retention in atherosclerosis","volume":"287","author":"Didangelos","year":"2012","journal-title":"J. Biol. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/17\/9328\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:54:22Z","timestamp":1760165662000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/17\/9328"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,28]]},"references-count":113,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms22179328"],"URL":"https:\/\/doi.org\/10.3390\/ijms22179328","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,28]]}}}