Positive and negative regulators of osteoclast apoptosis

Abstract

Survival and apoptosis are of major importance in the osteoclast life cycle. As osteoclasts have short lifespan, any alteration that prolongs their viability may cause enhanced osteoclast activity. Hence, the regulation of OC apoptosis has been recognized as a critical factor in bone remodeling. An imbalance in bone remodeling due to increased osteoclast activity leads to most adult bone diseases such as osteoporosis, rheumatoid arthritis and multiple myeloma. Therefore, manipulating osteoclast death would be a viable therapeutic approach in ameliorating bone diseases, with accelerated resorption. Over the last few decades we have witnessed the unraveling of many of the intracellular mechanisms responsible for osteoclast apoptosis. Thus, an understanding of the underlying mechanisms by which osteoclasts undergo programmed cell death and the regulators that modulate that activity will undoubtedly provide an insight into the development of pharmacological agents to treat such pathological bone diseases.

Keywords: Apoptosis; Estrogen; FAS/FASL system; Osteoclasts; TRAIL/TRAILR system.

Fig. 1

Signaling pathways in osteoclast (OC) differentiation, survival and death. Binding of RANKL to RANK results in the recruitment of adaptor molecules such as the TNFR-associated factors (TRAFs) and activation of several downstream signaling pathways. The RANKL-RANK complex can activate all three MAPK pathways and the NF-κB pathway, by interacting with TRAF6 and TGF-α activated kinase (TAK)-1. Activation of the JNK pathway mobilizes a number of osteoclastogenic transcription factors such as c-Fos, Fos-related antigens (Fra-1and 2) and the nuclear factor-activated T-cells (NFAT) c1. Both the NF-κB and the JNK signaling pathways are essential for OC differentiation. Binding of TNF-α to TNFR has a strong synergistic effect with RANK in NF-κB and JNK pathways through RIP-IKK activation. The RANKL-RANK-mediated interaction of TRAF6 with c-Src stimulates the PI3K-Akt pathway necessary for cell survival. M-CSF binding to its cognate receptor, c-Fms, and its association with c-Src and PI3K acts synergistically on the PI3K-Akt pathway necessary for OC survival. Binding of Ras to c-Fms activates the Ras and Raf/MEK/ERK pathways as well. PAK1 is activated by M-CSF in a Ras-dependent mechanism that promotes OC survival. PAK1 promotes OC survival by modulating expression of the IAP family member, Survivin.