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Fibrin Accumulation Secondary to Loss of Plasmin‐Mediated Fibrinolysis Drives Inflammatory Osteoporosis in Mice
Author(s) -
Cole Heather A.,
Ohba Tetsuro,
Nyman Jeffry S.,
Hirotaka Haro,
Cates Justin M. M.,
Flick Matthew J.,
Degen Jay L.,
Schoenecker Jonathan G.
Publication year - 2014
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.38639
Subject(s) - fibrin , fibrinogen , plasmin , inflammation , endocrinology , fibrinolysis , osteoporosis , medicine , immunology , chemistry , biochemistry , enzyme
Objective 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‐related comorbidities, we undertook this study to test the hypothesis that persistent fibrin deposition causes inflammatory osteoporosis. Methods 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‐deficient mice that were concomitantly either fibrinogen deficient or carrying a mutant form of fibrinogen lacking the α M β 2 binding motif. Results 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)‐mediated activation of osteoclasts via activation of the leukocyte integrin receptor α M β 2 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 α M β 2 binding motif prevented the degenerative skeletal phenotypes, resulting in normal local and systemic cytokine levels. Conclusion Taken together, these data reveal for the first time that fibrin promotes inflammation‐driven systemic osteoporosis, which suggests a novel association between hemostasis, inflammation, and bone biology.