Geranylgeraniol Restores Zoledronic Acid-Induced Efferocytosis Inhibition in Bisphosphonate-Related Osteonecrosis of the Jaw

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.

The Role of Geranylgeraniol in Managing Bisphosphonate-Related Osteonecrosis of the Jaw

“…In the study of Chen et al, male C57BL/6J mice (4-week-old) were given zoledronate (250 μg/kg, i. p.) twice a week and their first maxillary molar were extracted 1 week after zoledronate treatment. GGOH (250 μg/kg) was administered together with zoledronate after tooth extraction for 4 weeks ( Chen et al, 2021 ). Zoledronate stimulates osteocyte and pre-osteoblast apoptosis in mice and suppressed efferocytosis of macrophages on apoptotic cells ( Chen et al, 2021 ).…”

“…GGOH (250 μg/kg) was administered together with zoledronate after tooth extraction for 4 weeks ( Chen et al, 2021 ). Zoledronate stimulates osteocyte and pre-osteoblast apoptosis in mice and suppressed efferocytosis of macrophages on apoptotic cells ( Chen et al, 2021 ). GGOH reverse the negative effects of zoledronate on efferocytosis by restoring Rac1 homeostasis and shuttling Rac1 at the cellular membrane.…”

“…GGOH reverse the negative effects of zoledronate on efferocytosis by restoring Rac1 homeostasis and shuttling Rac1 at the cellular membrane. Consequently, GGOH reduces osteocytic apoptosis at the alveolar crest and improves bone healing of the tooth sockets in mice ( Chen et al, 2021 ). This is the only study that investigates the protective effects of GGOH on osteocytes under the influence of bisphosphonates.…”

Potential therapeutic role of spermine via Rac1 in osteoporosis: Insights from zebrafish and mice

“…In contrast, the role of Rac1 on bone homeostasis in GIOP has rarely been reported. Some studies have suggested that imbalance or abnormal function of Rac1 will negatively impact the skeletal system, regardless of whether it is up-regulated or down-regulated ( Chen et al, 2021 ; Mäkitie et al, 2021 ). In this study, SPM induced the expression of Rac1, suppressing bone resorption and facilitating bone formation.…”

Biodegradable Dual-Function Nanocomposite Hydrogels for Prevention of Bisphosphonate-Related Osteonecrosis of the Jaw

“…In addition, we have recently shown that GGOH could preserve a pool of viable MSCs with osteogenic potency against ZA and suggested GGOH as a promising agent for BRONJ prevention − A systemic application of GGOH may interfere with the therapeutic benefit of N-BPs at the other bony sites, while local irrigation or delivery without a control release carrier requires nonpractically frequent GGOH applications. A well sustained release system for local delivery of GGOH may be more practical to prevent BRONJ and promote better jawbone healing after bony surgery.…”