Investigating the role of complement 5a in systemic bone loss after myocardial infarction

Myocardial infarction (MI) and osteoporotic fracture are two of the leading causes of morbidity and mortality worldwide. We have previously established that MI in mice directly causes post-traumatic systemic bone loss and that the sympathetic nervous system plays a role in this response. However, the systemic injury response is mediated by multiple systems. In this study, we investigated the role of complement 5a (C5a), one of the main mediators driving multiple organ dysfunction after trauma. MI was surgically induced in 12-week-old male C57BL/6 J mice (B6/J), C5a receptor 1 knockout mice (C5aR1^−/−) and B10·D2-Hc0 H2d H2-T18c/oSnJ (B10·D2), (JAX Strain # 000461) mice that are deficient in serum C5. Systemic and localized bone changes were analyzed at 7-, 14- and 28-days post-MI using micro-computed tomography and three-point bending mechanical testing. Osteoclast number and activity was quantified using tartrate-resistant acid phosphatase (TRAP) staining, and voluntary activity levels were measured using open field. We found that MI induced peak trabecular bone loss 7 days after injury in the L5 vertebral body and caused reductions in femoral cortical bone 28 days post-MI. However, MI did not impact femoral trabecular bone in this timeframe. B10·D2 mice had reduced trabecular and cortical bone morphology compared to B6 and C5aR1^−/− mice, but did not exhibit an altered response to MI. Osteoclast activity 7-days post-MI was increased in C5aR1^−/− mice compared to B6 and B10·D2 mice, but MI did not impact osteoclast activity at this time point. Altogether, these findings suggest that C5a may influence overall response to MI and bone morphology instead of post-traumatic systemic bone loss response following MI, though likely not as a primary mechanism.