Dr. Nyman has a patent application pending for a system and method for determining mechanical properties of bone structures.
Fibrin Accumulation Secondary to Loss of Plasmin-Mediated Fibrinolysis Drives Inflammatory Osteoporosis in Mice
Version of Record online: 28 JUL 2014
Copyright © 2014 by the American College of Rheumatology
Arthritis & Rheumatology
Volume 66, Issue 8, pages 2222–2233, August 2014
How to Cite
Cole, H. A., Ohba, T., Nyman, J. S., Hirotaka, H., Cates, J. M. M., Flick, M. J., Degen, J. L. and Schoenecker, J. G. (2014), Fibrin Accumulation Secondary to Loss of Plasmin-Mediated Fibrinolysis Drives Inflammatory Osteoporosis in Mice. Arthritis & Rheumatology, 66: 2222–2233. doi: 10.1002/art.38639
- Issue online: 28 JUL 2014
- Version of Record online: 28 JUL 2014
- Accepted manuscript online: 24 MAR 2014 12:00AM EST
- Manuscript Accepted: 18 MAR 2014
- Manuscript Received: 17 OCT 2013
- Orthopaedic Research and Education Foundation
- Musculoskeletal Transplantation Foundation
- Caitlin Lovejoy Fund
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.
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 αMβ2 binding motif.
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 αMβ2 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 αMβ2 binding motif prevented the degenerative skeletal phenotypes, resulting in normal local and systemic cytokine levels.
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.