The Delicate Balancing Act

For this article, Laura DeFrancesco interviewed Lorenz Hofbauer, head of the Molecular Bone Biology Laboratory at Philipps University, Marburg, Germany; Colin Dunstan, senior research scientist, Amgen Inc., in Thousand Oaks, Calif., and Sundeep Khosla, professor of medicine, Mayo Medical School. Data from the Web of Science show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. L.C. Hofbauer, S. Khosla, C.R. Dunstan, et al., "The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption," Journal of Bone and Mineral Research,15:2-12, January 2000. (Cited in 102 papers) Osteoblasts and osteoclasts do a delicate dance to keep bone formation and bone resorption, respectively, in balance. Upset this equilibrium, and at one extreme, osteoporosis develops, a common malady that decreases bone mass, while at the other extreme, osteopetrosis occurs, a rare but troublesome condition that increases bone density. The need for balance has been appreciated for sometime; nearly 50 factors can influence bone metabolism, though how exactly they do this was not known. In 1997, two groups, almost simultaneously, discovered an element critical to keeping bone formation and resorption in balance. Since then, the picture has come into focus."This has been the biggest discovery in the last 10 years in the bone area," says Colin Dunstan, senior scientist at Amgen Inc., Thousand Oaks, Calif. In this paper Dunstan, along with Lorenz Hofbauer, head of the Molecular Bone Biology Laboratory at Philipps University, Marburg, Germany, and Sundeep Khosla, professor of medicine, Mayo Medical School, pulled together the various strings that keep bone formation and resorption balanced. Searching for the Elusive Before the discovery, biologists studying bone formation were stymied by the inability to reproduce the effects in vitro that hormones and cytokines have on bone resorption in vivo. Parathyroid hormone, for example, mobilizes calcium from bone to maintain normal calcium levels. Yet, if parathyroid hormone is applied to osteoclasts in vitro, nothing happens. Stromal or other fibroblast-like cells must be cocultured for osteoclasts to respond to parathyroid hormone. Obviously, signaling exists between the two cell types, but discovering the signal's mediator was elusive. The breakthrough came when Amgen scientists completed a genome screen for novel secreted proteins. Dunstan remembers a member of the tumor necrosis factor (TNF) superfamily that was unremarkable until his team looked at X-rays of transgenic mice overexpressing it. Surprisingly, they found that while these animals appeared normal, they had profound osteopetrosis. The researchers then showed that this protein blocked osteoclast differentiation by preventing bone resorption.1 Accordingly, they named the protein osteoprotegerin (OPG). A few months later, Japanese scientists at the Snow Brand Milk Company reported isolating the same protein.2 Once osteoprotegerin was found, both groups used it to fish out other proteins in the pathway, starting with its partner on stromal cell membranes.3,4 Both groups came up with TRANCE (TNR-related activation induced cytokine), also known as RANKL (receptor activator of NF-*B ligand). This ligand had previously been associated with T-cells and dendritic cells, but this work was the first to demonstrate activity on bone cells, Dunstan says. The last puzzle piece fell quickly into place, as the relevant receptor for RANK ligand, RANK, was immediately located on osteoclasts and their precursors.5 Focus on the Future A regulatory scheme emerged in which osteoblasts and osteoclasts interact through RANKL (blasts) and RANK (clasts) sending osteoclast precursors down the path to differentiation and activation, unless OPG is present. By binding to RANKL, OPG acts as a decoy receptor, preventing osteoclast formation, and hence sparing bone. While studies continue to learn how the different signals work, Mayo Clinic and Amgen researchers are moving into human studies. Khosla is investigating the connection between sex hormones and bone formation by looking at the effects of estrogens and testosterones on the OPG/RANK/RANKL pathway. Amgen scientists are studying the molecule's therapeutic potential. In a phase I clinical study, they showed that a single injection of recombinant OPG given to post-menopausal women slowed the rate of bone turnover for weeks following treatment.6 Hofbauer foresees the potential to treat people with bone malignancies that cause painful fractures. Tumors, he explains, could have either high levels of RANK ligand or low levels of OPG, which would activate osteoclasts. When the ostoclasts digest bone, free space in bone is created, providing room for tumor growth. One strategy might be to block osteoclast activation with OPG, and block tumor progression in bone. "This," Hofbauer says, "is more exciting than osteoporosis, which is an important disease but where there are effective treatments. With bone cancer, the condition is more severe, and the only treatments are invasive." Laura DeFrancesco (defrancesco1@earthlink.net) is a freelance writer in Pasadena, Calif. References 1. W.S. Simonet et al., "Osteoprotegerin: A novel secreted protein involved in the regulation of bone density," Cell, 89:309-19, 1997. 2. H. Yasuda et al., "Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): A mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro," Endocrinology, 139:1329-37, 1998. 3. D.L. Lacey et al., "Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation, Cell, 93:165-76, 1998. 4. H. Yasuda et al., "Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL," Proceedings of the National Academy of Sciences (PNAS), 95:3597-602, 1998. 5. H. Hsu et al., "Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand," PNAS, 96:3540-5, 1999. 6. P.J. Bekker et al., "The effect of a single dose of osteoprotegerin in postmenopausal women," Journal of Bone and Mineral Research, 16:348-60, February 2001.

The Delicate Balancing Act

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