{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T22:13:24Z","timestamp":1791152004886,"version":"4.1.0"},"reference-count":42,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2014,7,28]],"date-time":"2014-07-28T00:00:00Z","timestamp":1406505600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100001279","name":"Orthopaedic Research and Education Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001279","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2014,8]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Osteoporosis is a skeletal disorder characterized by low bone mass and increased bone fragility associated with aging, menopause, smoking, obesity, or diabetes. Persistent inflammation has been identified as an instigating factor in progressive bone loss. In addition to the role of fibrin in coagulation, inordinate fibrin deposition within a tissue matrix results in increased local inflammation. Given that fibrin accumulation is a hallmark of osteoporosis\u2010related comorbidities, we undertook this study to test the hypothesis that persistent fibrin deposition causes inflammatory osteoporosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Multiple imaging modalities, bone integrity metrics, and histologic analyses were employed to evaluate skeletal derangements in relation to fibrin deposition, circulating fibrinogen levels, and systemic markers of inflammation in mice that were plasminogen deficient and in plasminogen\u2010deficient mice that were concomitantly either fibrinogen deficient or carrying a mutant form of fibrinogen lacking the \u03b1\n                      <jats:sub>M<\/jats:sub>\n                      \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      binding motif.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Mice generated with a genetic deficit in the key fibrinolytic protease, plasmin, uniformly developed severe osteoporosis. Furthermore, the development of osteoporosis was fibrin(ogen) dependent, and the derangements in the bone remodeling unit were mechanistically tied to fibrin(ogen)\u2010mediated activation of osteoclasts via activation of the leukocyte integrin receptor \u03b1\n                      <jats:sub>M<\/jats:sub>\n                      \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      on monocytes and secondary stimulation of osteoblasts by RANKL. Notably, the genetic elimination of fibrin(ogen) or the expression of a mutant form of fibrinogen retaining clotting function but lacking the \u03b1\n                      <jats:sub>M<\/jats:sub>\n                      \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      binding motif prevented the degenerative skeletal phenotypes, resulting in normal local and systemic cytokine levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Taken together, these data reveal for the first time that fibrin promotes inflammation\u2010driven systemic osteoporosis, which suggests a novel association between hemostasis, inflammation, and bone biology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.38639","type":"journal-article","created":{"date-parts":[[2014,3,24]],"date-time":"2014-03-24T23:16:24Z","timestamp":1395702984000},"page":"2222-2233","source":"Crossref","is-referenced-by-count":44,"title":["Fibrin Accumulation Secondary to Loss of Plasmin\u2010Mediated Fibrinolysis Drives Inflammatory Osteoporosis in Mice"],"prefix":"10.1002","volume":"66","author":[{"given":"Heather A.","family":"Cole","sequence":"first","affiliation":[{"name":"Vanderbilt University Medical Center Nashville Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuro","family":"Ohba","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center Nashville Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffry S.","family":"Nyman","sequence":"additional","affiliation":[{"name":"Vanderbilt University, Vanderbilt University Medical Center, and VA Tennessee Valley Healthcare System Nashville Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haro","family":"Hirotaka","sequence":"additional","affiliation":[{"name":"University of Yamanashi Yamanashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin M. 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