Osteoclast differentiation

YAMAGISHI T, OTSUKA E and HAGIWARA H (2001) Reciprocal control of expression of mRNAs for osteoclast differentiation factor and OPG in osteogenic stromal cells by genistein evidence for the involvement of topoisomerase 11 in osteoclastogenesis. Endocrinol 142, 3632-7. 

Interleukin 1 (IL-1) is produced mainly by activated monocytes-macropha-ges, and its principal action is to stimulate thymocytes. A pleiotropic cytokine, IL-1 induces the expression of a large diversity of cytokines such as IL-6, leukaemia inhibitory factor (LIF), and other proinflammatory molecules (Di-marello 1994). IL-1 and TNF-a carry out as part of their function increasing the expression of NF-/cB and JNK (c-Jun N-terminal kinase). The importance of IL-1 in OCS is demonstrated because the IL-1-receptor-deficient mouse is resistant to ovariectomy (OVX)-induced bone loss (Lorenzo et al. 1998). The importance in pathological bone loss is also illustrated by the fact that treatment with IL-1 receptor antagonist slows down bone erosion for patients affected with rheumatoid arthritis (Kwan et al. 2004). IL-1 increases osteoclast differentiation rather than mature osteoclast activity, and infusion of IL-1 into mice induces hypercalcemia and bone resorption. Finally, IL-1 and TNF-a... 

Lacey DL, Timms E, Tan HL, KelleyMJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ (1998) Osteo-protegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93 165-176... 

Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423 337-342... 

Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Morinaga T, Fligashio K, Martin TJ, Suda T (2000) Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med 191 275-286... 

Suda T, Takahashi N, Martin TJ (1992) Modulation of osteoclast differentiation. Endocr... 

Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ (1999) Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 20 345-357... 

Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, Tan HL, Elliott G, Kelley MJ, Sarosi I, Wang L, Xia XZ, Elliott R, Chiu L, Black T, Scully S, Capparelli C, Morony S, Shimamoto G, Bass MB, Boyle WJ (1999) Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA 96 3540-3545... 

Shevde NK, Bendixen AC, Dienger KM, Pike JW (2000) Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression. Proc Natl Acad Sci USA 97 7829-7834... 

Gao YH, Shinki T, YuasaT, Kataoka-Enomoto H, Komori T, Suda T, Yamaguchi A (1998) Potential role of cbfal, an essential transcriptional factor for osteoblast differentiation, in osteoclastogenesis regulation of mRNA expression of osteoclast differentiation factor (ODF). BioChem Biophys Res Commun 252 697-702... 

Quinn JM, Itoh K, Udagawa N, Hausler K, Yasuda H, Shima N, Mizuno A, Higashio K, Takahashi N, Suda T, Martin TJ, Gillespie MT (2001) Transforming growth factor beta affects osteoclast differentiation via direct and indirect actions. J Bone Miner Res 16 1787-1794... 

Osteoclast differentiation Raw264, bone marrow macrophages, hematopoetic stem cells Rankl Comparison of response markers across models to identify common mechanisms [23]... 

The study of osteoclast differentiation is important for understanding potential new treatments for osteoporosis. Such therapies are typically explored in tissue culture models such as the Raw264 mouse monocytic cell line, which is capable of differentiation into functional multinuclear osteoclasts after treatment with the cytokine Rankl. Use of transformed cell lines raises the concern that results may not be extrapolated to normal tissue. To address this question, the transcriptional responses for Rankl treatment of the Raw264 cell line, and of two ex vivo primary cell systems (bone marrow macrophages, and hematopoetic stem cells) were compared using Affymetrix GeneChips [23]. The models proved to... 

Seales EC, Micoli KJ, McDonald JM, Calmodulin is a critical regulator of osteoclastic differentiation, function, and survival, / Cell Biochem 97 45—55, 2006. 

Strontium ranelate has not been approved in the United States for the treatment of osteoporosis but is being used in Europe, generally at a dose of 2 g/d. Denosumab, an antibody to RANKL that suppresses bone resorption by interfering with RANKL/RANK induction of osteoclast differentiation and function, has shown good efficacy in phase 3 trials and may be approved for clinical use in the near future. 

Suda, N., Morita, I., Kuroda, T., and Murota, S. 1993. Participation of oxidative stress in the process of osteoclast differentiation. Biochim. Biophys. Acta 1157, 318-323. 

Symbioimines Inhibitors of Osteoclast Differentiation and Cyclooxygenase Activity... 

Kita, M., Kondo, M., Koyama, T, Yamada, K., Matsumoto, T, Lee, K.H., Woo, J.T., and Uemura, D. 2004. Symbioimine exhibiting inhibitory effect of osteoclast differentiation, from the symbiotic marine dinofiagellate Symbiodinium sp. JAm Chem Soc 126, 4794 795. 

Recently, two products of the osteoblast have been identified that appear to be the final common pathway in coordinating osteoblast and osteoclast activity. The first, receptor activator of nuclear factor-KB (RANK) ligand, binds to a receptor on osteoclast progenitor cells and increases osteoclast differentiation and activity. The second, osteo-protegerin (OPG), serves as a decoy receptor for RANK ligand. When OPG binds to RANK ligand, the osteoclast-stimulation activity is prevented. The relative ratios of these two molecules determine bone turnover. 

Fig. 10.1 Osteoclasts tunneling. Osteoclasts differentiate at cracks in the bone and form a tunnel (lacuna) containing a central capillary surrounded by connective tissue. Fibroblast-like precursors of osteoblasts are activated to become osteoblasts and new bone is formed (Modified from Fig. 22.54 in The Molecular Biology of the Cell. B. Alberts et al., 4th Ed. 2002. Garland Science, Taylor Francis Group, New York)...

Osteoblasts around bony microcracks are induced to express two cytokines monocyte Colony Stimulating Factor (mCSF) which is secreted and Osteoclast Differentiating Factor (ODF) which is mainly on the cell surface. The mCSF stimulates microcrack-adherent monocytes to proliferate and fuse into large multinucleated cells (preosteoclasts) that express Osteoclast Differentiation and Activation Receptor (ODAR). 

Fig. 10.5 Osteoclast differentiation factors. Osteoblasts make monocyte colony stimulating factor (mCSF) that induces bone adherent monocytes carrying the corresponding receptor (mCSF Receptor) to fuse into osteoclast precursors (preosteoclasts). Preosteoclasts develop within the periosteum and are detectable by their expression of the osteoclast differentiation and activation receptor (ODAR). Osteoblasts also make cell-membrane bound and soluble osteoclast differentiation factors (ODF and sODF) that react with ODAR to cause preosteoclast differentiation. Finally, osteoblasts make osteoclast inhibition factor (OCIF), also called osteoprotegerin, which acts as an ODF decoy receptor and prevents ODF or sODF reacting with ODAR. ODAR is commonly referred to as RANK and ODF as the RANK ligand (RANKL) in the literature (see text)...

Osteoclast differentiation factor RANK ligand Osteoprotegerin ligand TNF-related activation-induced cytokine... 

Osteoclast differentiation and activation receptor Receptor activator of NFkB TNF superfamily receptor 11A... 

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