{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:22:41Z","timestamp":1780536161470,"version":"3.54.1"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T00:00:00Z","timestamp":1638748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01GM126062-01A1"],"award-info":[{"award-number":["1R01GM126062-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1S10OD021804-01A1"],"award-info":[{"award-number":["1S10OD021804-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["2P30 CA068485-14"],"award-info":[{"award-number":["2P30 CA068485-14"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5U24DK059637-13"],"award-info":[{"award-number":["5U24DK059637-13"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10RR027631"],"award-info":[{"award-number":["S10RR027631"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32GM007628"],"award-info":[{"award-number":["T32GM007628"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013017","name":"Vanderbilt University Medical Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013017","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>Chronic diseases in growing children, such as autoimmune disorders, obesity, and cancer, are hallmarked by musculoskeletal growth disturbances and osteoporosis. Many of the skeletal changes in these children are thought to be secondary to chronic inflammation. Recent studies have likewise suggested that changes in coagulation and fibrinolysis may contribute to musculoskeletal growth disturbances. In prior work, we demonstrated that mice deficient in plasminogen, the principal protease of degrading and clearing fibrin matrices, suffer from inflammation-driven systemic osteoporosis and that elimination of fibrinogen resulted in normalization of IL-6 levels and complete rescue of the skeletal phenotype. Given the intimate link between coagulation, fibrinolysis, and inflammation, here we determined if persistent fibrin deposition, elevated IL-6, or both contribute to early skeletal aging and physeal disruption in chronic inflammatory conditions. Skeletal growth as well as bone quality, physeal development, and vascularity were analyzed in C57BL6\/J mice with plasminogen deficiency with and without deficiencies of either fibrinogen or IL-6. Elimination of fibrinogen, but not IL-6, rescued the skeletal phenotype and growth disturbances in this model of chronic disease. Furthermore, the skeletal phenotypes directly correlated with both systemic and local vascular changes in the skeletal environment. In conclusion, these results suggest that fibrinolysis through plasmin is essential for skeletal growth and maintenance, and is multifactorial by limiting inflammation and preserving vasculature.<\/jats:p>","DOI":"10.3389\/fcvm.2021.768338","type":"journal-article","created":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T05:36:57Z","timestamp":1638769017000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["The Deleterious Effects of Impaired Fibrinolysis on Skeletal Development Are Dependent on Fibrin(ogen), but Independent of Interlukin-6"],"prefix":"10.3389","volume":"8","author":[{"given":"Heather A.","family":"Cole","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie N.","family":"Moore-Lotridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory D.","family":"Hawley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Jacobson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Yuasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Gewin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffry S.","family":"Nyman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Flick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan G.","family":"Schoenecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.ocl.2010.08.005","article-title":"Obesity in pediatric orthopaedics","volume":"42","author":"Gettys","year":"2011","journal-title":"Orthop Clin North Am."},{"key":"B2","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1203\/01.pdr.0000214966.60416.1b","article-title":"Impaired growth plate chondrogenesis in children with chronic illnesses","volume":"59","author":"De Luca","year":"2006","journal-title":"Pediatr Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1680","DOI":"10.1359\/jbmr.1999.14.10.1680","article-title":"Growth retardation in children with chronic renal failure","volume":"14","author":"Kuizon","year":"1999","journal-title":"J Bone Miner Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1159\/000064756","article-title":"Fundamental mechanisms of growth failure in inflammatory bowel disease","volume":"58","author":"Ballinger","year":"2002","journal-title":"Horm Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1097\/01241398-199211000-00020","article-title":"Long-term effects of neonatal bone and joint infection on adjacent growth plates","volume":"12","author":"Peters","year":"1992","journal-title":"J Pediatr Orthop."},{"key":"B6","doi-asserted-by":"publisher","first-page":"E37","DOI":"10.1542\/peds.103.3.e37","article-title":"Growth failure after treatment of pediatric brain tumors","volume":"103","author":"Clarson","year":"1999","journal-title":"Pediatrics."},{"key":"B7","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/j.ecl.2016.01.009","article-title":"Update on bone health in pediatric chronic disease","volume":"45","author":"Williams","year":"2016","journal-title":"Endocrinol Metab Clin North Am."},{"key":"B8","doi-asserted-by":"publisher","first-page":"3551","DOI":"10.1002\/art.22175","article-title":"Impaired skeletal development in interleukin-6-transgenic mice: a model for the impact of chronic inflammation on the growing skeletal system","volume":"54","author":"De Benedetti","year":"2006","journal-title":"Arthritis Rheum."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1056\/NEJMoa1107477","article-title":"C-reactive protein, fibrinogen, and cardiovascular disease prediction","volume":"367","author":"Collaboration","year":"2012","journal-title":"New Engl J Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2222","DOI":"10.1002\/art.38639","article-title":"Fibrin accumulation secondary to loss of plasmin-mediated fibrinolysis drives inflammatory osteoporosis in mice","volume":"66","author":"Cole","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1242\/dev.130807","article-title":"Cartilage to bone transformation during fracture healing is coordinated by the invading vasculature and induction of the core pluripotency genes","volume":"144","author":"Hu","year":"2017","journal-title":"Development."},{"key":"B12","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/j.bone.2012.10.011","article-title":"Differential development of the distal and proximal femoral epiphysis and physis in mice","volume":"52","author":"Cole","year":"2013","journal-title":"Bone."},{"key":"B13","doi-asserted-by":"publisher","first-page":"H302","DOI":"10.1152\/ajpheart.00928.2003","article-title":"Quantitative microcomputed tomography analysis of collateral vessel development after ischemic injury","volume":"287","author":"Duvall","year":"2004","journal-title":"Am J Physiol Heart Circ Physiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e0198088","DOI":"10.1371\/journal.pone.0198088","article-title":"Unexpected timely fracture union in matrix metalloproteinase 9 deficient mice","volume":"13","author":"Yuasa","year":"2018","journal-title":"PLoS ONE."},{"key":"B15","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/j.bone.2014.07.002","article-title":"The temporal and spatial development of vascularity in a healing displaced fracture","volume":"67","author":"Yuasa","year":"2014","journal-title":"Bone."},{"key":"B16","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1101\/gad.9.7.794","article-title":"Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction","volume":"9","author":"Bugge","year":"1995","journal-title":"Genes Dev."},{"key":"B17","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/S0092-8674(00)81390-2","article-title":"Loss of fibrinogen rescues mice from the pleiotropic effects of plasminogen deficiency","volume":"87","author":"Bugge","year":"1996","journal-title":"Cell."},{"key":"B18","doi-asserted-by":"publisher","first-page":"5899","DOI":"10.1073\/pnas.93.12.5899","article-title":"Urokinase-type plasminogen activator is effective in fibrin clearance in the absence of its receptor or tissue-type plasminogen activator","volume":"93","author":"Bugge","year":"1996","journal-title":"Proc Natl Acad Sci USA."},{"key":"B19","doi-asserted-by":"publisher","first-page":"232","DOI":"10.3390\/cells8030232","article-title":"Signals from the niche: insights into the role of IGF-1 and IL-6 in modulating skeletal muscle fibrosis","volume":"8","author":"Forcina","year":"2019","journal-title":"Cells."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e13512","DOI":"10.1111\/apha.13512","article-title":"Plasminogen deficiency does not prevent sodium retention in a genetic mouse model of experimental nephrotic syndrome","volume":"231","author":"Xiao","year":"2021","journal-title":"Acta Physiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1007\/s00424-017-2014-y","article-title":"Physiology and pathophysiology of the plasminogen system in the kidney","volume":"469","author":"Svenningsen","year":"2017","journal-title":"Eur J Physiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1177\/0972753119900630","article-title":"Fibrinogen and LDL influence on blood viscosity and outcome of acute ischemic stroke patients in Indonesia","volume":"26","author":"Rasyid","year":"2019","journal-title":"Ann Neurosci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/0049-3848(76)90044-X","article-title":"Relationship between fibrinogen and blood viscosity","volume":"8","author":"Matsuda","year":"1976","journal-title":"Thrombosis Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1161\/01.CIR.87.6.1915","article-title":"Blood viscosity, fibrinogen, and activation of coagulation and leukocytes in peripheral arterial disease and the normal population in the Edinburgh Artery Study","volume":"87","author":"Lowe","year":"1993","journal-title":"Circulation."},{"key":"B25","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1055\/s-0038-1651881","article-title":"The relationship of plasma fibrinogen, erythrocyte flexibility and blood viscosity","volume":"38","author":"Dupont","year":"1977","journal-title":"Thromb Haemost."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1748-1716.2009.02037.x","article-title":"Mechanisms of fibrinogen-induced microvascular dysfunction during cardiovascular disease","volume":"198","author":"Lominadze","year":"2010","journal-title":"Acta Physiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/j.bbrc.2011.07.133","article-title":"Fibrinogen alters mouse brain endothelial cell layer integrity affecting vascular endothelial cadherin","volume":"413","author":"Muradashvili","year":"2011","journal-title":"Biochem Biophys Res Commun."},{"key":"B28","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1002\/jcp.21845","article-title":"Fibrinogen induces alterations of endothelial cell tight junction proteins","volume":"221","author":"Patibandla","year":"2009","journal-title":"J Cell Physiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1007\/s11010-007-9579-2","article-title":"Fibrinogen induces endothelial cell permeability","volume":"307","author":"Tyagi","year":"2008","journal-title":"Mol Cell Biochem."},{"key":"B30","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1302\/0301-620X.43B4.800","article-title":"The vascular contribution to osteogenesis. IV. The effect of pressure upon the epiphysial cartilage of the rabbit","author":"Trueta","year":"1961","journal-title":"J Bone Joint Surg Br."},{"key":"B31","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1302\/0301-620X.42B3.571","article-title":"The vascular contribution to osteogenesis. III. Changes in the growth cartilage caused by experimentally induced ischaemia","author":"Trueta","year":"1960","journal-title":"J Bone Joint Surg Br."},{"key":"B32","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1302\/0301-620X.45B3.572","article-title":"The vascular contribution to osteogenesis. V. The vasculature supplying the epiphysial cartilage in rachitic rats","volume":"45","author":"Trueta","year":"1963","journal-title":"J Bone Joint Surg Br."},{"key":"B33","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1038\/368339a0","article-title":"Impaired immune and acute-phase responses in interleukin-6-deficient mice","volume":"368","author":"Kopf","year":"1994","journal-title":"Nature."},{"key":"B34","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1042\/bj2650621","article-title":"Interleukin-6 and the acute phase response","volume":"265","author":"Heinrich","year":"1990","journal-title":"Biochem J."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1084\/jem.180.4.1243","article-title":"Defective inflammatory response in interleukin 6-deficient mice","volume":"180","author":"Fattori","year":"1994","journal-title":"J Exp Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"8","DOI":"10.3321\/j.issn:1002-0098.2008.01.004","article-title":"Effect of fibrinogen on the secretion of interleukin-1beta and - 8 by polymorphonuclear leukocytes","volume":"43","author":"Ge","year":"2008","journal-title":"Chin J Stomatol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1165\/ajrcmb.20.5.3281","article-title":"Transcriptional regulation of the interleukin-1 \u03b2 promoter via fibrinogen engagement of the CD18 integrin receptor","volume":"20","author":"Perez","year":"1999","journal-title":"Am J Respir Cell Mol Biol."}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2021.768338\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T05:37:04Z","timestamp":1638769024000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2021.768338\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,6]]},"references-count":37,"alternative-id":["10.3389\/fcvm.2021.768338"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2021.768338","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,6]]},"article-number":"768338"}}