Impairment of early fracture healing by skeletal muscle trauma is restored by FK506

Abstract

Background: Heightened local inflammation due to muscle trauma or disease is associated with impaired bone regeneration. Methods: We hypothesized that FK506, an FDA approved immunomodulatory compound with neurotrophic and osteogenic effects, will rescue the early phase of fracture healing which is impaired by concomitant muscle trauma in male (~4 months old) Lewis rats. FK506 (1 mg/kg; i.p.) or saline was administered systemically for 14 days after an endogenously healing tibia osteotomy was created and fixed with an intermedullary pin, and the overlying tibialis anterior (TA) muscle was either left uninjured or incurred volumetric muscle loss injury (6 mm full thickness biopsy from middle third of the muscle). Results: The salient observations of this study were that 1) concomitant TA muscle trauma impaired recovery of tibia mechanical properties 28 days post-injury, 2) FK506 administration rescued the recovery of tibia mechanical properties in the presence of concomitant TA muscle trauma but did not augment mechanical recovery of an isolated osteotomy (no muscle trauma), 3) T lymphocytes and macrophage presence within the traumatized musculature were heightened by trauma and attenuated by FK506 3 days post-injury, and 4) T lymphocyte but not macrophage presence within the fracture callus were attenuated by FK506 at 14 days post-injury. FK506 did not improve TA muscle isometric torque production

Autologous minced muscle grafts improve endogenous fracture healing and muscle strength after musculoskeletal trauma

“…Additionally, VML injury induced elevation of DAMPs and in turn monocytes in the systemic circulation lend further support to VML injury protracting fracture site inflammation and disrupting fracture healing (Hurtgen et al. , ).…”

“…; Hurtgen et al. , ). Specifically, rodent TA VML injury has been shown to increase macrophage and T‐lymphocyte infiltration within the injured muscle and at the fracture site of the adjacent tibia and to delay recovery of tibia mechanical properties, which was ameliorated by systemic administration of the immunosuppressant drug FK506 (Hurtgen et al.…”

“…Specifically, rodent TA VML injury has been shown to increase macrophage and T‐lymphocyte infiltration within the injured muscle and at the fracture site of the adjacent tibia and to delay recovery of tibia mechanical properties, which was ameliorated by systemic administration of the immunosuppressant drug FK506 (Hurtgen et al. , ). Given that muscle injuries that present canonical immune and regenerative responses have been reported to not ultimately impair fracture healing (Kase et al.…”

“…Additionally, rodent polytrauma involving blunt chest trauma impairs femur fracture healing, which may be rescued by inhibition of immune Complement activation (Recknagel et al 2011Claes et al 2012;Weckbach et al 2012). Local exacerbated skeletal muscle inflammation has also been shown to impair nearby bone repair in dystrophic mice and after TA muscle VML injury (Abou-Khalil et al 2014;Hurtgen et al 2016Hurtgen et al , 2017. Specifically, rodent TA VML injury has been shown to increase macrophage and T-lymphocyte infiltration within the injured muscle and at the fracture site of the adjacent tibia and to delay recovery of tibia mechanical properties, which was ameliorated by systemic administration of the immunosuppressant drug FK506 (Hurtgen et al 2016(Hurtgen et al , 2017.…”

Effects of BMP‐2 dose and delivery of microvascular fragments on healing of bone defects with concomitant volumetric muscle loss

“…9 Our model recapitulates the clinical observation of impaired bone healing when concomitant soft tissue injury is present, and this has also been seen in similar pre-clinical models of composite tissue injury. 9,[24][25][26] In this study, we tested the hypotheses that BMP-2-mediated functional regeneration of composite extremity injuries is dose dependent and can be further enhanced via co-delivery of adipose-derived microvascular fragments (MVF), which have been previously shown to increase tissue vascular volume.…”