Osteoprotegerin Reverses Osteoporosis by Inhibiting Endosteal Osteoclasts and Prevents Vascular Calcification by Blocking a Process Resembling Osteoclastogenesis
Hosung Min,Sean Morony,Ildiko Sarosi,Colin R. Dunstan,Casey Capparelli,Sheila Scully,Gwyneth Van,Steve Kaufman,Paul J. Kostenuik,David L. Lacey,William J. Boyle,W. Scott Simonet +11 more
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TLDR
Findings indicate that the OPG/OPGL/RANK signaling pathway may play an important role in both pathological and physiological calcification processes and may also explain the observed high clinical incidence of vascular calcification in the osteoporotic patient population.Abstract:
High systemic levels of osteoprotegerin (OPG) in OPG transgenic mice cause osteopetrosis with normal tooth eruption and bone elongation and inhibit the development and activity of endosteal, but not periosteal, osteoclasts. We demonstrate that both intravenous injection of recombinant OPG protein and transgenic overexpression of OPG in OPG−/2 mice effectively rescue the osteoporotic bone phenotype observed in OPG-deficient mice. However, intravenous injection of recombinant OPG over a 4-wk period could not reverse the arterial calcification observed in OPG−/− mice. In contrast, transgenic OPG delivered from mid-gestation through adulthood does prevent the formation of arterial calcification in OPG−/− mice. Although OPG is normally expressed in arteries, OPG ligand (OPGL) and receptor activator of NF-κB (RANK) are not detected in the arterial walls of wild-type adult mice. Interestingly, OPGL and RANK transcripts are detected in the calcified arteries of OPG−/− mice. Furthermore, RANK transcript expression coincides with the presence of multinuclear osteoclast-like cells. These findings indicate that the OPG/OPGL/RANK signaling pathway may play an important role in both pathological and physiological calcification processes. Such findings may also explain the observed high clinical incidence of vascular calcification in the osteoporotic patient population.read more
Citations
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Clinical Implications of the Osteoprotegerin/RANKL/RANK System for Bone and Vascular Diseases
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References
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Journal ArticleDOI
Osteoprotegerin Ligand Is a Cytokine that Regulates Osteoclast Differentiation and Activation
David L. Lacey,Emma Timms,Hong-Lin Tan,Michael J. Kelley,Colin R. Dunstan,Tim Burgess,Robin Elliott,Anne Colombero,Gary Elliott,S. Scully,Hailing Hsu,John K. Sullivan,Nessa Hawkins,E. Davy,C. Capparelli,Alana Eli,Yi-xin Qian,Steve Kaufman,Ildiko Sarosi,Victoria Shalhoub,Giorgio Senaldi,Jane Guo,John M. Delaney,William J. Boyle +23 more
TL;DR: The effects of OPGL are blocked in vitro and in vivo by OPG, suggesting that OPGl and OPG are key extracellular regulators of osteoclast development.
Journal ArticleDOI
Osteoprotegerin: A Novel Secreted Protein Involved in the Regulation of Bone Density
William S. Simonet,David L. Lacey,Colin R. Dunstan,Michael J. Kelley,Ming-Shi Chang,R Lüthy,Hung Q. Nguyen,S Wooden,L Bennett,Tom Boone,Grant Shimamoto,Margaret L. DeRose,Robin Elliott,Anne Colombero,Hong-Lin Tan,Geraldine Trail,John K. Sullivan,E. Davy,N. Bucay,L Renshaw-Gegg,T.M Hughes,Dave Hill,W Pattison,Patricia Shehan Campbell,S Sander,Gwyneth Van,John E. Tarpley,P Derby,Richard Lee,William J. Boyle +29 more
TL;DR: Data show that OPG can act as a soluble factor in the regulation of bone mass and imply a utility for OPG in the treatment of osteoporosis associated with increased osteoclast activity.
Journal ArticleDOI
Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL
Hisataka Yasuda,Nobuyuki Shima,Nobuaki Nakagawa,Kyoji Yamaguchi,Masahiko Kinosaki,Shin Ichi Mochizuki,Akihiro Tomoyasu,Kazuki Yano,Masaaki Goto,Akihiko Murakami,Eisuke Tsuda,Tomonori Morinaga,Kanji Higashio,Nobuyuki Udagawa,Naoyuki Takahashi,Tatsuo Suda +15 more
TL;DR: In this article, a membrane-bound osteoclast differentiation factor (ODF) was found to induce OCL formation from osteoblasts/stromal cells in the presence of bone-resorbing factors.
Journal ArticleDOI
OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis
Young-Yun Kong,Hiroki Yoshida,Ildiko Sarosi,Hong-Lin Tan,Emma Timms,Casey Capparelli,Sean Morony,Antonio J. Oliveira-dos-Santos,Gwyneth Van,Annick Itie,Wilson Khoo,Andrew Wakeham,Colin R. Dunstan,David L. Lacey,Tak W. Mak,William J. Boyle,Josef M. Penninger +16 more
TL;DR: OPGL is a new regulator of lymph-node organogenesis and lymphocyte development and is an essential osteoclast differentiation factor in vivo.
Journal ArticleDOI
osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification
N. Bucay,Ildiko Sarosi,Colin R. Dunstan,Sean Morony,John E. Tarpley,C. Capparelli,S. Scully,Hong Lin Tan,Weilong Xu,David L. Lacey,William J. Boyle,William S. Simonet +11 more
TL;DR: It is demonstrated that OPG is a critical regulator of postnatal bone mass and regulation of OPG, its signaling pathway, or its ligand(s) may play a role in the long observed association between osteoporosis and vascular calcification.
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