Plasminogen activation in the musculoskeletal acute phase response: Injury, repair, and disease

Abstract

The musculoskeletal system is critical for movement and the protection of organs. In addition to abrupt injuries, daily physical demands inflict minor injuries, necessitating a coordinated process of repair referred to as the acute-phase response (APR). Dysfunctional APRs caused by severe injuries or underlying chronic diseases are implicated in pathologic musculoskeletal repair, resulting in decreased mobility and chronic pain. The molecular mechanisms behind these phenomena are not well understood, hindering the development of clinical solutions. Recent studies indicate that, in addition to regulating intravascular clotting, the coagulation and fibrinolytic systems are also entrenched in tissue repair. Although plasmin and fibrin are considered antithetical to one another in the context of hemostasis, in a proper APR, they complement one another within a coordinated spatiotemporal framework. Once a wound is contained by fibrin, activation of plasmin promotes the removal of fibrin and stimulates angiogenesis, tissue remodeling, and tissue regeneration. Insufficient fibrin deposition or excessive plasmin-mediated fibrinolysis in early convalescence prevents injury containment, causing bleeding. Alternatively, excess fibrin deposition and/or inefficient plasmin activity later in convalescence impairs musculoskeletal repair, resulting in tissue fibrosis and osteoporosis, while inappropriate fibrin or plasmin activity in a synovial joint can cause arthritis. Together, these pathologic conditions lead to chronic pain, poor mobility, and diminished quality of life. In this review, we discuss both fibrin-dependent and -independent roles of plasminogen activation in the musculoskeletal APR, how dysregulation of these mechanisms promote musculoskeletal degeneration, and the possibility of therapeutically manipulating plasmin or fibrin to treat musculoskeletal disease. K E Y W O R D S acute-phase reaction, fibrinogen, musculoskeletal diseases, plasminogen, plasminogen activators, rheumatic diseases 470 | GIBSON et al. Essentials• Musculoskeletal disease results in pain and poor mobility with limited treatment options.• Beyond clot degredation, plasmin is essential for musculoskeletal health.• Inappropriate plasmin activity in disease can drive musculoskeletal degeneration.• The plasminogen activation system presents new potential targets to treat musculoskeletal disease.

Effects of microgravity exposure and fructo-oligosaccharide ingestion on the proteome of soleus and extensor digitorum longus muscles in developing mice

“…Activation of blood coagulation and innate immune response was indicated in Sol muscles of mice exposed to μ- g , regardless of FOS ingestion (Table 8 and Supplementary Tables 3a and 4a ), which had not been reported in previous studies 16 , 37 . In addition to these biological processes, fibrinolysis is also reportedly activated in response to skeletal muscle injury and has important role in the initial phase of repair 48 – 52 . However, negative regulation of fibrinolysis was indicated, especially in Sol muscles of mice exposed to μ- g without FOS ingestion, by the significant increase in Apoh, Plg, Serpinf2, and Hrg (Table 8 and Supplementary Table 3a ).…”

“…This result could be attributed to differences in the time of activation of these processes. One of the important roles of fibrinolysis is to remove fibrin deposited after blood coagulation for subsequent tissue repair, thus blood coagulation precedes the activation of fibrinolysis 48 . These results suggested that Sol muscles of mice exposed to μ- g were injured by gravitational reloading.…”

Severe injury-induced osteoporosis and skeletal muscle mineralization: Are these related complications?

“…Due to advances in critical care medicine, patients now survive severe injuries, such as burn, blast, or polytraumatic injuries, that were once considered fatal. While being fortunate to survive, many patient experience complications during convalescence, including poor tissue repair, and hemostasis ( Gibson et al, 2020 ; Alessandrino and Balconi, 2013 ; Smith et al, 2000 ; Ferguson et al, 2008 ). While severely injured 2 patients are beleaguered by a variety of systemic derangements, one of the more paradoxical complications involves the dysregulation of biomineralization ( Muschitz et al, 2017 ; Klein, 2006 ; Vanden Bossche and Vanderstraeten, 2005 ; Dey et al, 2017 ).…”

“…Following an injury, the acute phase response (APR) is activated in proportion to the injury severity ( Gibson et al, 2020 ; Benvenuti et al, 2017 ; Baker et al, 2018 ). To ensure survival, the APR first activates coagulation and an acute inflammatory response to stop bleeding and prevent infection.…”

“…To ensure survival, the APR first activates coagulation and an acute inflammatory response to stop bleeding and prevent infection. Proportional to the amount of tissue injury, an exuberant survival inflammatory response following a severe injury can drive systemic changes in the musculoskeletal system ( Gibson et al, 2020 ; Baker et al, 2018 ; Klein, 2019 ). Both pre-clinical and clinical studies have examined the molecular connections between traumatic injuries and hypermetabolism, skeletal muscle wasting, and rapid bone turnover ( Klein, 2019 ; Pereira et al, 2005 ; Klein, 2015 ; Auger et al, 2017 ; Hew et al, 2020 ; Stanojcic et al, 2018 ).…”