RANK Ligand is a critical mediator in bone remodeling
Balancing resorption and formation in healthy bone
In healthy adults, bone physiology is a dynamic, coordinated process controlled by 2 types of cells: osteoclasts and osteoblasts (see Figure 1). Through a balanced remodeling process, osteoclasts resorb bone and osteoblasts build bone at the same site.1,2
Figure 1
This image shows osteoclasts and osteoblasts in normal bone (toluidine blue, x100). The large osteoclast is actively resorbing bone. Osteoblasts are small, cuboid cells that actively lay down bone matrix.1
Copyright David W. Dempster, PhD, 2000.
This bone remodeling sequence consists of 4 distinct phases: activation, resorption, reversal, and formation.
RANK Ligand is essential to the development and activation of bone-resorbing osteoclasts2-7
Several members of the tumor necrosis factor (TNF) superfamily of proteins are key participants in the complex series of events that results in the ability of mature osteoclasts to resorb bone. RANK, RANK Ligand, and osteoprotegerin (OPG) all work together to help regulate osteoclast function.2
Expressed by osteoblasts and stromal cells, RANK Ligand binds to the RANK receptor on osteoclast precursors to set in motion their differentiation into (mature) osteoclasts (See Figure 2).1,3,6 When this occurs, prefusion osteoclasts mature to multinucleated osteoclasts.1,2 At the bone surface, RANK Ligand activates the osteoclasts and suppresses apoptosis.4,8
Figure 2
RANK Ligand and OPG balance bone loss and formation
Several factors can initiate osteoclast formation, including parathyroid hormone, prostaglandins, interleukin-1 and -6, and colony-stimulating factors; most of these, however, stimulate osteoclastogenesis by up-regulating the expression of RANK Ligand on the surface of marrow stromal cells and immature osteoblasts.1
To maintain the balance between bone formation and bone resorption, the body naturally produces OPG, another member of the TNF superfamily of proteins secreted by osteoblasts. By binding with RANK Ligand, OPG prevents RANK Ligand from binding with RANK on the surface of osteoclasts and their precursors. This process is governed by cytokines and hormones, and ultimately determines osteoclast activity.2,7,9 Seen in this light, OPG is important in the regulation of osteoclast formation and bone resorption.2,4,6,7,9
Increased RANK Ligand expression is key to the development of bone diseases that result from increased bone resorption. Often, OPG expression is decreased and/or RANK Ligand expression is increased. Increased RANK Ligand expression promotes bone loss, whereas decreased RANK Ligand activity reduces osteoclast activity and bone resorption.2,7
Read more about increased RANK Ligand signaling in:
Fuller K, Wong B, Fox S, Choi Y, Chambers TJ. TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med. 1998;188:997-1001.
Lacey DL, Tan HL, Lu J, et al. Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo. Am J Pathol. 2000;157:435-448.
Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93:165-176.
Yasuda H, Shima N, Nagakawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA. 1998;95:3597-3602.
Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA. 2004;292:490-495.
O'Brien EA, Williams JHH, Marshall MJ. Osteoprotegrin ligand regulates osteoclast adherence to the bone surface in mouse calvaria. Biochem Biophys Res Comm. 2000;274:281-290.
Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89:309-319.
