The vital osteoclast: how is it regulated?

Abstract

Bone is a rigid but dynamic organ. Once formed, it is continually broken down and reformed by the co-ordinated actions of osteoclasts (that mediate resorption) and osteoblasts (that mediate formation) on trabecular bone surfaces and in the Haversian systems of cortical bone. Any net change in bone mass therefore reflects a change in the balance between these two processes. If osteoclastic bone resorption exceeds the bone-forming capacity of osteoblasts, the result is osteoporosis, but if the opposite occurs the result is osteopetrosis. This remodelling occurs in focal and discrete packets -bone-remodelling units -throughout the skeleton. As the remodelling that occurs in each unit is geographically and chronologically separated from other units of remodelling, it is thought that activation of the sequence of cellular events responsible is locally controlled, probably by paracrine signalling in the bone microenvironment.All diseases of bone are superimposed on this normal cellular remodelling process. Most are due to excess osteoclastic activity, which leads to an imbalance in bone remodelling that favours resorption. The past 5 years have witnessed important insights into osteoclast biology. Much of this new information has come from the analysis of a family of biologically related tumour necrosis factor (TNF) receptor (TNFR)/TNF-like proteins -osteoprotegerin (OPG), receptor activator of nuclear factor (NF)-kB (RANK) and RANK ligand (RANKL) -which together regulate osteoclast differentiation. 1Osteoclasts are derived from the monocyte/macrophage lineage, and proliferation and survival of their precursors depend on the cytokine macrophage colony-stimulating factor (M-CSF). Activation of RANK by osteoblast-expressed RANKL commits the precursors to the osteoclast fate. OPG is a soluble decoy receptor that competes with RANK for binding to RANKL. Studies of this pathway have clarified how diverse physiological and pathophysiological signals exert their effects on osteoclast formation, function and survival, and ultimately control skeletal remodelling and bone mass. Two papers 3,4 in the current issue of Cell Death and Differentiation further extend our understanding of osteoclast formation and survival. The paper by Yang et al.3 proposes a new role for decoy receptor 3 (DcR3) in regulating osteoclastogenic differentiation of haematopoietic precursor cells, whereas the paper by Luegmayr et al. raises the possibility that osteoclast function and survival are regulated by exogenous cholesterol/lipoprotein levels. In the following, these findings are briefly discussed in their respective contexts.In addition to M-CSF and RANKL, pro-inflammatory cytokines -TNF-a in particular -have been shown to have crucial roles in osteoclast differentiation. Oestrogen deficiency induces bone loss as a result of alterations in cytokine expression that either directly or indirectly modulate osteoclasts and their precursors, and thereby increase resorption. TNF receptor 1 (TNFR1)-deficient mice are not responsive to oestrogen depletion,...

Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss

“…In addition to RANKL-[Ca 2+ ] i oscillation-NFATc1 pathway, Rgs12 also regulates c-fos expression; this suggested that Rgs12 may be involved in RANKL-JNK-c-Fos pathway. 43 Overexpression of NFAT2 partially restored the differentiation ability and Cathepsin K expression but not c-Fos expression in Rgs12-deficient OC precursor cells. This is supported by the findings from Takayanagi et al that NFAT2 cooperates with c-Fos to lead to OC differentiation and that overexpression of NFAT2 can only partially restore the osteoclastogenesis in NFAT2-mutant cells.…”

Environmental pH-controlled loading and release of protein on mesoporous hydroxyapatite nanoparticles for bone tissue engineering

“…The MHA adsorbed OPG in specific pH environments exhibits a sustained release pattern in this acid environment (Scheme 2). The activation of RANK would be prevented by OPG binding to RANKL and OPG can also induce apoptosis of osteoclast [33][34][35].…”

“…The local pH around the ruffled border of osteoclasts is from 4.0 to 5.0 [31,32]. Osteoprotegerin (OPG), which belongs to the tumor necrosis factor (TNF) receptor superfamily [33], is known to negatively regulate osteoclast maturation and activation and to promote apoptosis [33][34][35]. Realizing the controlled release of OPG under acid conditions is very promising.…”

Inhibitory effects of osteoprotegerin on osteoclast formation and function under serum-free conditions

“…One example is OPG, which belongs to the tumor necrosis factor (TNF) receptor superfamily [32]. OPG is known to negatively regulate osteoclast maturation and activation [1]. This factor initially acts as a decoy receptor and prevents the interaction of RANKL with RANK, thereby curbing the activity, survival, and proliferation of osteoclasts [22].…”