RANKL increases the level of Mcl-1 in osteoclasts and reduces bisphosphonate-induced osteoclast apoptosis in vitro

Abstract

Introduction Bisphosphonates are the most widely used class of drug for inhibiting osteoclast-mediated bone loss, but their effectiveness at preventing joint destruction in rheumatoid arthritis has generally been disappointing. We examined whether the ability of bisphosphonates to induce osteoclast apoptosis and inhibit bone resorption in vitro is influenced by the cytokine receptor activator of nuclear factor-kappa B ligand (RANKL), an important mediator of inflammation-induced bone loss.

Combination of alendronate and genistein synergistically suppresses osteoclastic differentiation of RAW267.4 cells in vitro

“…This effect was observed with an alendronate concentration of 100 µM, which induced the apoptosis of rabbit osteoclasts in vitro (28). In the present study, combinations of alendronate and genistein with lower concentrations were found to synergistically inhibit the RANKL-induced osteoclastic differentiation of RAW267.4 cells in vitro.…”

“…Bisphosphonates have been shown to have a direct suppressive effect on osteoclasts (6,7,28). This effect was observed with an alendronate concentration of 100 µM, which induced the apoptosis of rabbit osteoclasts in vitro (28).…”

Bone remodelling at a glance

“…Normally, osteoclasts die by apoptosis, a process that involves signalling pathways that include extracellular-signal-regulated kinase (ERK), the serine/threonine protein kinase Akt and mammalian target of rapamycin (mTOR), which regulate the expression of apoptotic factors, such as B-cell lymphoma-extra large (BclX L ), the BH3-only family member Bim and myeloid cell leukaemia sequence 1 (Mcl-1) (Akiyama et al, 2003;Xing and Boyce, 2005;Bradley et al, 2008;Sutherland et al, 2009). However, osteoclast survival is thought to be increased in pathological conditions that are associated with increased osteoclast numbers, such as Paget's disease of bone (Chamoux et al, 2009).…”

“…Non-canonical Wnt signalling mediates the commitment of mesenchymal stem cells to the osteoblast lineage by preventing the expression of peroxisome proliferator activated receptor- (PPAR), which is required for adipocyte differentiation (Takada et al, 2007). Osteoporosis and reduced levels of circulating oestrogen are associated with a switch that favours adipocytic over osteoblastic development (Rosen et al, 2009).…”

Pharmacodynamics of bisphosphonates in arthritis

“…Sutherland et al have recently shown that RANKL and TNF-alpha were also able to prevent apoptosis induced by the nitrogen-containing BP alendronate and clodronate by increasing the expression of the anti-apoptotic protein Mcl-1 by the osteoclasts [12]. The importance of those cytokines in the focal and systemic bone loss associated with arthritis could explain the lack of efficacy of BPs in this indication.…”