Review Article

Osteoprotegerin-Receptor Activator of Nuclear Factor-κB Ligand Ratio: A New Approach to Osteoporosis Treatment?

Authors: Magdalena Coetzee, MSC, Marlena C. Kruger, PHD

Abstract

Osteoporosis, the most commonly occurring bone disease, is characterized by enhanced bone fragility and increased risk of fracture. Bone remodeling is the process in which bone is broken down by osteoclasts and then built back again by osteoblasts. In healthy adult bone, these two processes are balanced and a constant level of bone mass is maintained. Some of the proteins involved in the interaction between osteoblasts and osteoclasts have recently been identified. Receptor activator of nuclear factor-κB (RANK) ligand is produced by osteoblasts and exerts its effects through binding to its receptor (RANK) on osteoclast precursor cells. Binding results in activation of osteoclasts. Osteoblasts also produce osteoprotegerin (OPG), a potent inhibitor of osteoclast formation and a decoy receptor for RANK. The relative ratio of OPG and RANK ligand in the bone marrow microenvironment may determine the number of active osteoclasts, bone resorption rate, and bone mass. OPG is currently under investigation for osteoporosis treatment.

This content is limited to qualifying members.

Existing members, please login first

If you have an existing account please login now to access this article or view purchase options.

Purchase only this article ($25)

Create a free account, then purchase this article to download or access it online for 24 hours.

Purchase an SMJ online subscription ($75)

Create a free account, then purchase a subscription to get complete access to all articles for a full year.

Purchase a membership plan (fees vary)

Premium members can access all articles plus recieve many more benefits. View all membership plans and benefit packages.

References

1. Inzerillo AM, Zaidi M. Osteoporosis: Trends and intervention. Mt Sinai J Med 2002;69:220–231.
 
2. Looker AC, Orwoll ES, Johnston CC, et al. Prevalence of low femoral bone density in older U.S. adults from NHANES III. J Bone Miner Res 1997;12:1761–1768.
 
3. Consensus Development Conference, Hong Kong, April 1–2, 1993. Am J Med 1993;95:1S–78S.
 
4. Raisz LG. Physiology and pathophysiology of bone remodeling. Clin Chem 1999;45:1353–1358.
 
5. Dempster DW, Cosman F, Parisien M, et al. Anabolic actions of parathyroid hormone on bone.Endocr Rev 1993;14:690–709.
 
6. Turner RT, Riggs BL, Spelsberg TC. Skeletal effects of estrogen. Endocr Rev 1994;15:275–300.
 
7. Jimi E, Nakamura I, Amano H, et al. Osteoclast function is activated by osteoblastic cells through a mechanism involving cell-to-cell contact. Endocrinology 1996;137:2187–2190.
 
8. Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A 1998;95:3597–3602.
 
9. 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.
 
10. Akatsu T, Murakami T, Nishikawa M, et al. Osteoclastogenesis inhibitory factor suppresses osteoclast survival by interfering in the interaction of stromal cells with osteoclast. Biochem Biophys Res Commun 1998;250:229–234.
 
11. Emery JG, McDonnell P, Burke MB, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 1998;273:14363–14367.
 
12. The American Society for Bone and Mineral Research President's Committee on Nomenclature. Proposed standard nomenclature for new tumor necrosis factor members involved in the regulation of bone resorption. Bone 2000;27:761–764.
 
13. Mizuno A, Amizuka N, Irie K, et al. Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun 1998;247:610–615.
 
14. Kong YY, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999;397:315–323.
 
15. Li J, Sarosi I, Yan XQ, et al. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci U S A2000;97:1566–1571.
 
16. Suda T, Takahashi N, Udagawa N, et al. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 1999;20:345–357.
 
17. Hofbauer LC, Dunstan CR, Spelsberg TC, et al. Osteoprotegerin production by human osteoblast lineage cells is stimulated by vitamin D, bone morphogenic protein-2, and cytokines. Biochem Biophys Res Commun 1998;250:776–781.
 
18. Hofbauer LC, Khosla S, Dunstan CR, et al. Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. Endocrinology 1999;140:4367–4370.
 
19. Saika M, Inoue D, Kido S, et al. 17β-Estradiol stimulates expression of osteoprotegerin by a mouse stromal cell line, ST-2, via estrogen receptor-α. Endocrinology 2001;142:2205–2212.
 
20. Riggs BL. The mechanisms of estrogen regulation of bone resorption. J Clin Invest 2000;106:1203–1204.
 
21. Horwood NJ, Elliott J, Martin TJ, et al. Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells. Endocrinology 1998;139:4743–4746.
 
22. Lee SK, Lorenzo JA. Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: Correlation with osteoclast-like cell formation. Endocrinology 1999;140:3552–3561.
 
23. Onyia JE, Miles RR, Yang X, et al. In vivo demonstration that human parathyroid hormone 1-38 inhibits the expression of osteoprotegerin in bone with the kinetics of an immediate early gene. J Bone Miner Res 2000;15:863–871.
 
24. Kawaguchi H, Pilbeam CC, Harrison JR, et al. The role of prostaglandins in the regulation of bone metabolism. Clin Orthop 1995;313:36–46.
 
25. Akatsu T, Takahashi N, Debari K, et al. Prostaglandins promote osteoclastlike cell formation by a mechanism involving cyclic adenosine 3′, 5′-monophosphate in mouse bone marrow cell cultures. J Bone Miner Res 1989;4:29–35.
 
26. Nakashima T, Kobayashi Y, Yamasaki S, et al. Protein expression and functional difference of membrane-bound and soluble receptor activator of NF-κB ligand: Modulation of the expression by osteotropic factors and cytokines. Biochem Biophys Res Commun 2000;275:768–775.
 
27. Brändström H, Björkman T, Ljunggren O. Regulation of osteoprotegerin secretion from primary cultures of human bone marrow stromal cells. Biochem Biophys Res Commun 2001;280:831–835.
 
28. Masferrer JL, Zweifel BS, Manning PT, et al. Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic. Proc Natl Acad Sci U S A 1994;91:3228–3232.
 
29. Marshall MJ, Holt I, Davie MW. Inhibition of prostaglandin synthesis leads to a change in adherence of mouse osteoclasts from bone to periosteum. Calcif Tissue Int 1996;59:207–213.
 
30. O'Brien EA, Williams JH, Marshall MJ. Osteoprotegerin is produced when prostaglandin synthesis is inhibited causing osteoclasts to detach from the surface of mouse parietal bone and attach to the endocranial membrane. Bone 2001;28:208–214.
 
31. Hofbauer LC, Gori F, Riggs BL, et al. Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: Potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 1999;140:4382–4389.
 
32. Vidal NO, Brändström H, Jonsson KB, et al. Osteoprotegerin mRNA is expressed in primary human osteoblast-like cells: Down-regulation by glucocorticoids. J Endocrinol 1998;159:191–195.
 
33. Hofbauer LC, Khosla S, Dunstan CR, et al. The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res 2000;15:2–12.
 
34. Yano K, Tsuda E, Washida N, et al. Immunological characterization of circulating osteoprotegerin/osteoclastogenesis inhibitory factor: Increased serum concentrations in postmenopausal women with osteoporosis. J Bone Miner Res 1999;14:518–527.
 
35. Browner WS, Lui LY, Cummings SR. Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women. J Clin Endocrinol Metab 2001;86:631–637.
 
36. Fazzalari NL, Kuliwaba JS, Atkins GJ, et al. The ratio of messenger RNA levels of receptor activator of nuclear factor κB ligand to osteoprotegerin correlates with bone remodeling indices in normal human cancellous bone but not in osteoarthritis. J Bone Miner Res 2001;16:1015–1027.
 
37. Seck T, Diel I, Bismar H, et al. Serum parathyroid hormone, but not menopausal status, is associated with the expression of osteoprotegerin and RANKL mRNA in human bone samples. Eur J Endocrinol 2001;145:199–205.
 
38. Kostenuik PJ, Capparelli C, Morony S, et al. OPG and PTH-(1-34) have additive effects on bone density and mechanical strength in osteopenic ovariectomized rats. Endocrinology 2001;142:4295–4304.
 
39. Yamamoto M, Murakami T, Nishikawa M, et al. Hypocalcemic effect of osteoclastogenesis inhibitory factor/osteoprotegerin in the thyroparathyroidectomized rat. Endocrinology 1998;139:4012–4015.
 
40. Bekker PJ, Holloway D, Nakanishi A, et al. The effect of a single dose of osteoprotegerin in postmenopausal women. J Bone Miner Res 2001;16:348–360.