Abstract
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe side effect of long-term administration of bisphosphonates such as zoledronic acid (ZA), but its pathogenesis remains unclear. Impairment of the clearance of apoptotic cells (termed “efferocytosis”) by ZA may be associated with the pathogenesis of BRONJ. The aim of this study was to investigate whether ZA might inhibit macrophage efferocytosis and promote osteocytic apoptosis, and the underlying mechanisms responsible for the disturbing balance between clean and generation of osteocytic apoptosis. We found that ZA significantly promoted the apoptosis of osteocyte and pre-osteoblast via BRONJ mouse models and in vitro MC3T3-E1 but also inhibited the efferocytosis of macrophage on apoptotic cells. Moreover, supplement with geranylgeraniol (GGOH), a substrate analog for geranylgeranylation of Rac1, could restore Rac1 homeostasis and rescue macrophage efferocytosis. GGOH partially inhibits MC3T3-E1 apoptosis induced by ZA via downregulation of Rac1/JNK pathway. We also examined the Rac1 distribution and activation conditions in bone marrow-derived macrophages (BMDMs) and MC3T3-E1 under ZA treatment, and we found that ZA impaired Rac1 migration to BMDM membrane, leading to round appearance with less pseudopodia and efferocytosis inhibition. Moreover, ZA simultaneously activated Rac1, causing overexpression of P-JNK and cleaved caspase 3 in MC3T3-E1. Finally, the systemic administration of GGOH decreased the osteocytic apoptosis and improved the bone healing of the extraction sockets in BRONJ mouse models. Taken together, our findings provided a new insight and experimental basis for the application of GGOH in the treatment of BRONJ.
Highlights
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is one serious complication of long-term use of bisphosphonates, such as zoledronic acid (ZA) (Singh and Gonegandla, 2020)
We aimed to investigate whether GGOH can neutralize the negative effects of ZA in terms of osteocytic apoptosis and macrophage efferocytosis, which may provide a new insight for the treatment of BRONJ
The in vivo finding indicated that the balance between the generation and clearance of apoptotic cells (ACs) in BRONJ mouse models had been broken
Summary
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is one serious complication of long-term use of bisphosphonates, such as zoledronic acid (ZA) (Singh and Gonegandla, 2020). One billion apoptotic cells (ACs) are produced in an adult human every day (Boada-Romero et al, 2020; Doran et al, 2020). These cells can be cleaned up with very high efficiency to prevent accumulation of dead cells, secondary necrosis, and tissue inflammation (Boada-Romero et al, 2020). The clearance of ACs, termed “efferocytosis,” is one of the most important functions of professional phagocytes including macrophages (Zheng et al, 2021).
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