|For this article, Steve Bunk interviewed William J. Boyle, associate director, department of cell biology, Amgen, Thousand Oaks, Calif., and Tatsuo Suda, emeritus professor and dean, Showa University School of Dentistry, Tokyo, Japan. Data from the Web of Science (ISI, Philadelphia) show that these papers have been cited 50 to 100 times more often than the average paper of the same type and age. |
D.L. Lacey, E. Timms, H.-L. Tan, M.J. Kelley, C.R. Dunstan, T. Burgess, R. Elliott, A. Colombero, G. Elliott, S. Scully, H. Hsu, J. Sullivan, N. Hawkins, E. Davy, C. Capparelli, A. Eli, Y.-X. Qian, S. Kaufman, I. Sarosi, V. Shalhoub, G. Senaldi, J. Guo, J. Delaney, W.J. Boyle, "Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation," Cell, 93:165-76, 1998. (Cited in more than 174 papers since publication)
H. Yasuda, N. Shima, N. Nakagawa, K. Yamaguchi, M. Kinosaki, S.-I. Mochizuki, A. Tomoyasu, K. Yano, M. Goto, A. Murakami, E. Tsuda, T. Morinaga, K. Higashio, N. Udagawa, N. Takahashi, T. Suda, "Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL," Proceedings of the National Academy of Sciences, 95:3597-602, 1998. (Cited in more than 191 papers since publication)
Cells that do the excavation work or resorption of bone, removing organic matrix and mineral, are called osteoclasts. Cells that restore the lost tissue are osteoblasts. For bone remodeling to occur, osteoclast progenitor cells must differentiate into osteoclasts, a process modulated by cell-to-cell interactions with osteoblasts. These two papers both identified the cytokine that induces this differentiation, each giving it their own name.
Boyle's team dubbed it osteoprotegerin ligand (OPGL), because it binds to a receptor they had discovered the previous year and named osteoprotegerin (OPG).1 The word refers to the protein's role in protecting bone from destruction. Boyle's team found that OPG is a secreted protein, not a traditional surface membrane receptor, which suggested that it functioned in an extracellular milieu. They also identified OPG as a member of the tumor necrosis factor (TNF) receptor family. TNF is a proinflammatory cytokine that can cause the death of tumor cells. However, TNF also can contribute to such inflammatory diseases as rheumatoid arthritis and Crohn's disease. Boyle's group discerned that when OPGL binds to OPG, it counteracts the latter's protection of bone and starts the signaling that permits remodeling.
After the OPG paper appeared, scientists from the Snow Brand Milk Products Co. of Tochigi, Japan, published their isolation of a novel protein from human fibroblast culture that they called osteoclastogenesis inhibitory factor (OCIF).2 It proved to be identical to OPG. The Japanese researchers, led by Tatsuo Suda, now emeritus professor and dean, Showa University School of Dentistry, Tokyo, Japan, began pursuing a ligand and this time, they won a close race to publication against Boyle's team. They called the newfound protein osteoclast differentiation factor (ODF). It was the reward for a long search by Suda's team, which has been studying osteoclast biology for many years. "Based on our studies of osteoclast differentiation in vitro, we proposed the presence of a membrane-based factor to induce osteoclast differentiation called ODF in 1992," he recalls.
But the nomenclature for this vital ligand didn't end with ODF/OPGL. Both papers acknowledged work by two other groups that had appeared during preparation of their own reports. A multi- institutional U.S. team that was searching for apoptosis-regulating genes cloned a protein they named TNF-related activation-induced cytokine (TRANCE).3 Almost simultaneously, a group from Immunex Corp. in Seattle cloned a receptor from a cDNA library of human dendritic cells, which are essential for immune surveillance in many organs and tissues. Their name for the protein was receptor activator of NF*B (RANK).4 Inappropriate activation of NF*B, a nuclear factor, has been linked to inflammation, and its persistent inhibition can cause immune cell developmental problems, or even cell death. The Immunex team also isolated the RANK ligand, RANKL. They postulated that RANK and RANKL were important regulators of interactions between T cells and dendritic cells.
It turned out that RANK is the receptor for ODF/OPGL. Moreover, the latter two molecules are identical to RANKL and to TRANCE. Thus, the cytokine discovered by these two papers to be a key signaling mediator in bone remodeling now has the unwieldy acronym of ODF/OPGL/ TRANCE/RANKL. Boyle and Suda are part of a committee established by the American Society for Bone and Mineral Research to develop a more straightforward nomenclature. Results of those deliberations are to be published soon in four journals.
Boyle suspects the proteins also have a role in immune homeostasis, but that role is "certainly not central." He stresses, "What's important is regulation of relative amounts of OPG and OPGL. That determines how on or off the osteoclast pathway is." Suda believes, "ODF is also an important factor in the immune system, since both ODF-deficient and RANK-deficient mice completely lack peripheral lymph nodes."
In 1999, Boyle and colleagues showed that activated T cells can directly trigger osteoclastogenesis through OPGL, and that OPG treatment at the onset of adjuvant arthritis in rats can prevent crippling bone and cartilage destruction.5 They now are exploring signaling in the osteoclast pathway and regulatory mechanisms for osteoclast development, in search of new drug targets, especially for osteoclastogenesis inhibitors that could be taken orally.
Suda's team also is focusing on the signal transduction pathway, and on whether inflammatory bone resorption associated with rheumatoid arthritis and periodontal disease occurs through ODF/RANK signaling. "Very recently," he notes, "we reported that TNF* stimulates osteoclast differentiation by a mechanism independent of the ODF/RANK interaction."6
Steve Bunk (email@example.com) is a contributing editor for The Scientist.
1. W.S. Simonet et al., "Osteoprotegerin: a novel secreted protein involved in the regulation of bone density," Cell, 89:309-19, 1997.
2. E. Tsuda et al., "Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis," Biochemical and Biophysical Research Communications, 234:137-42, 1997.
3. B.R. Wong et al., "TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells," Journal of Biological Chemistry, 272:25190-4, 1997.
4. D.M. Anderson et al., "A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function," Nature, 390:175-9, 1997.
5. Y.Y. Kong et al., "Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand," Nature, 402:304-9, Nov. 18, 1999.
6. K. Kobayashi et al., "Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction," Journal of Experimental Medicine, 191:275-86, Jan. 17, 2000.