Alendronate induces osteoclast precursor apoptosis via peroxisomal dysfunction mediated ER stress

Abstract

Nitrogen-containing bisphosphonates including alendronate (ALN) are the current first line antiresorptive drug in treating osteoporosis. In our study, we found that ALN administration impaired the secretion of platelet derived growth factor-BB (PDGF-BB), the most important angiogenic cytokines produced by preosteoclast (POC), in both sham and ovariectomized (OVX) mice. To further understand this phenomenon, we induced bone marrow macrophages (BMMs) to POCs in vitro and detected the effects of ALN particularly in POCs. The proapoptotic effect of ALN in POCs was confirmed by flow cytometry. On the molecular level, we found that farnesyl diphosphate synthase (FDPS) inhibition of ALN led to peroxisomal dysfunction and up regulation of cytoprotective protein glucose-regulated protein (GRP) 78. Peroxisomal dysfunction further induced endoplasmic reticulum (ER) stress in POCs and finally resulted in cell apoptosis marked by reduced expression of B-cell lymphoma 2 (Bcl-2) and increased expressions of CCAAT/enhancer binding protein homologous protein (CHOP), Bcl2 associated X (Bax), and cleaved caspase-3. We concluded that ALN has no selectivity in inhibiting POC and mature osteoclast. For POCs, ALN inhibition of FDPS leads to peroxisomal dysfunction, which further mediates ER stress and finally causes cell apoptosis. Considering that decreased angiogenesis is also an important issue in treating osteoporosis, how to preserve pro-angiogenic POCs while depleting mature osteoclasts is a problem worthy to be solved.

4-Acetylantroquinonol B Inhibits Osteoclastogenesis by Inhibiting the Autophagy Pathway in a Simulated Microgravity Model

“…Cyclin D3 and cyclin E regulate the downstream pathways involved in osteoclast differentiation [ 46 ]. In our study, we showed that 4-AAQB activated apoptosis and caused cell cycle arrest at the G1-S phase, which is similar to the ALN mechanism [ 47 , 48 ]. Based on our findings, we suggest that 4-AAQB attenuates osteoclastogenesis by inducing cell apoptosis and causing cell cycle arrest at the G1-S phase.…”

“…Furthermore, in previous studies, autophagy was found to regulate cell apoptosis [ 52 ] and the cell cycle [ 53 ]. These signaling pathways have also been reported to participate in osteoclastogenesis [ 47 , 54 ]. Therefore, we concluded that 4-AAQB inhibits osteoclast differentiation by regulating autophagy to impact cell apoptosis and the cell cycle.…”

CircRNA_28313/miR-195a/CSF1 axis modulates osteoclast differentiation to affect OVX-induced bone absorption in mice

“…totally different functions from mature osteoblasts. Preosteoclast barely resorb bone matrix but could promote angiogenesis [13,37]. Therefore, depletion of mature osteoclasts while preserving preosteoclasts will be a more effective treatment strategy in osteoporosis.…”

Osteoclast-derived apoptotic bodies couple bone resorption and formation in bone remodeling

“…5d). To determine the key factors that govern the proangiogenic ability of pOC-ABs, we focused on PDGF-BB, which can be secreted by pOCs to induce the formation of CD31 hi Emcn hi endothelial cells 15,31 . Herein, we found that PDGF-BB was included in the proteomic signature of pOC-ABs and was rarely expressed in BMM-ABs or mOC-ABs (Fig.…”