Periprosthetic hypoxia as consequence of TRPM7 mediated cobalt influx in osteoblasts

The reasons for the high number of loosened metal-on-metal (MoM) hip implants are still not fully understood. Hypoxia-inducible factor 1 (HIF-1) mediated signaling pathways, which normally modulate tissue metabolism under hypoxic circumstances, could be triggered by metallic wear debris and influence bone metabolism favoring osteolysis. This may lead to early loosening of the orthopedic implants. Immunhistochemical staining of periprosthetic tissues of failed artificial hip implants showed that the concentration of HIF-1α in the surrounding tissues of failed MoM hip implants was significantly higher in comparison to failed metal-on-polyethylene (MoP) hip implants and osteoarthritic tissues. Therefore, we examined the Co²⁺ -uptake mechanisms and the influence of Co²⁺ uptake on HIF-1α stabilization. Based on cobalt mediated quenching effects, calcium imaging experiments using fura-2 showed a concentration-dependent cobalt influx in MG-63 cells, which could be inhibited by the unspecific TRPM7 channel inhibitor 2-APB (20 μM) and TRPM7 specific siRNA. Western blots confirmed a dose dependent increase of HIF-1α upon stimulation with Co²⁺ . This effect could be abrogated by inhibition of cobalt influx using 2-APB. This study shows that chemical hypoxia originating from HIF-1α upregulation within the periprosthetic tissue is related to cobalt wear debris and highlights TRPM7 as an important key mediator in this context. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1806-1813, 2019.