Trabecular Bone Loss at a Distant Skeletal Site Following Noninvasive Knee Injury in Mice

Traumatic injuries can have systemic consequences, as activation of the immune system and the early inflammatory response after trauma can lead to tissue destruction at sites not affected by the initial injury [1,2]. ACL rupture in humans causes an immediate flare of inflammatory cytokines [3,4] and biomarkers of cartilage damage [5–8] in the affected joint. Importantly, the increased matrix turnover observed after ACL injury may not be limited to the injured knee, as concentrations of aggrecan, cartilage oligomeric matrix protein, and matrix metalloproteinase-3 are also elevated in the uninjured knee of ACL rupture patients [9]. Similarly, surgically creating a tibial bone defect in rats increases the bone formation rate at distant, unrelated skeletal sites [10]. Altogether, these results suggest a possible systemic effect of musculoskeletal injuries that may be catabolic to the entire system. We have developed a noninvasive knee injury model in mice, which uses tibial compression overload to induce ACL injury [11]. The loading rate of this model can be controlled to create ACL injuries via either midsubstance tear or ligament rupture with an associated avulsion bone fracture [12]. We observed a 20–44% loss of trabecular bone mass in the femoral and tibial epiphysis of the affected limb by 7–14 days post-injury using this model. Significantly, we also observed a 3–12% decrease in BV/TV in the contralateral knee at 7 days post-injury relative to 1 day post-injury. This suggests that the injury in our mouse model could induce a systemic catabolic effect resulting in a loss of bone volume (and potentially bone strength) throughout the body. However, we have yet to investigate bone loss following acute knee injury at a distant, unrelated (non-contralateral) skeletal site. In the current study we utilized our noninvasive mouse knee injury model to determine whether acute knee injury causes a mechanically significant trabecular bone loss at a distant, unrelated skeletal site (L5 vertebral body). We quantified vertebral trabecular bone structure using high-resolution μCT, then determined differences in mechanical properties using FEM and compressive mechanical testing. We hypothesized that knee injury would initiate a loss of trabecular bone structure and strength at the L5 vertebral body. Results from this study reveal a novel and potentially important mechanism of systemic loss of bone structure and strength after musculoskeletal injury. Ultimately these data may affect the treatment of acute musculoskeletal injuries and the prevention of future bone fragility.