Journal ArticleDOI
Wnt signalling in osteoporosis: mechanisms and novel therapeutic approaches
TLDR
Experiments in mice have shown that downregulation or neutralization of Wnt antagonists enhances bone formation, and Phase II clinical trials show that 1-year treatment with antisclerostin antibodies increasesBone formation, decreases bone resorption and leads to a substantial increase in BMD.Abstract:
Osteoporosis is a skeletal disorder characterized by bone loss, which results in architectural deterioration of the skeleton, compromised bone strength and an increased risk of fragility fractures. Most current therapies for osteoporosis stabilize the skeleton by inhibiting bone resorption (antiresorptive agents), but the development of anabolic therapies that can increase bone formation and bone mass is of great interest. Wnt signalling induces differentiation of bone-forming cells (osteoblasts) and suppresses the development of bone-resorbing cells (osteoclasts). The Wnt pathway is controlled by antagonists that interact either directly with Wnt proteins or with Wnt co-receptors. The importance of Wnt signalling in bone formation is indicated by skeletal disorders such as sclerosteosis and van Buchem syndrome, which are caused by mutations in the gene encoding the Wnt antagonist sclerostin (SOST). Experiments in mice have shown that downregulation or neutralization of Wnt antagonists enhances bone formation. Phase II clinical trials show that 1-year treatment with antisclerostin antibodies increases bone formation, decreases bone resorption and leads to a substantial increase in BMD. Consequently, Wnt signalling can be targeted by the neutralization of its extracellular antagonists to obtain a skeletal anabolic response.read more
Citations
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Journal ArticleDOI
Osteoblast differentiation and bone matrix formation in vivo and in vitro
Harry C. Blair,Quitterie C. Larrouture,Yanan Li,Hang Lin,Donna Beer-Stoltz,Li Liu,Rocky S. Tuan,Lisa J. Robinson,Paul H. Schlesinger,Deborah J. Nelson +9 more
TL;DR: The characteristics of osteoblast differentiation and bone matrix synthesis are reviewed, which reveal a sophisticated proton export network driving mineralization, a gene expression program organized with the compartmentalization of the osteooblast epithelium that produces the mature bone matrix composite, despite varying serum calcium and phosphate.
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The role of the wnt/β-catenin signaling pathway in formation and maintenance of bone and teeth.
Peipei Duan,Lynda F. Bonewald +1 more
TL;DR: This pathway is not only important in mineralized tissue growth and development, but for modulation of the skeleton in response to loading and unloading and the viability and health of the adult and aging skeleton.
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MANAGEMENT OF ENDOCRINE DISEASE: Secondary osteoporosis: pathophysiology and management
Faryal S. Mirza,Ernesto Canalis +1 more
TL;DR: This review focuses on some of the common causes of osteoporosis, addressing the underlying mechanisms, diagnostic approach and treatment of low bone mass in the presence of these conditions.
Journal ArticleDOI
Notch Signaling and the Skeleton.
Stefano Zanotti,Ernesto Canalis +1 more
TL;DR: Notch plays a critical role in skeletal development and homeostasis, and serious skeletal disorders can be attributed to alterations in Notch signaling.
Journal ArticleDOI
The WNT system: background and its role in bone
TL;DR: The historical background to the discoveries of WNTs is provided, the different WNT signalling pathways are described and the current understanding of how these proteins regulate bone mass by affecting bone formation and resorption is summarized.
References
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Wnt/beta-catenin signaling in development and disease.
TL;DR: A remarkable interdisciplinary effort has unraveled the WNT (Wingless and INT-1) signal transduction cascade over the last two decades, finding that Germline mutations in the Wnt pathway cause several hereditary diseases, and somatic mutations are associated with cancer of the intestine and a variety of other tissues.
Journal ArticleDOI
Osteoporosis prevention, diagnosis, and therapy
Anne Klibanski,Lucile L. Adams-Campbell,Tamsen Bassford,Steven N. Blair,Scott D. Boden,Kay Dickersin,David R. Gifford,Lou Glasse,Steven R. Goldring,Keith A. Hruska,Susan R. Johnson,Laurie K. McCauley,William E. Russell +12 more
TL;DR: Though prevalent in white postmenopausal women, osteoporosis occurs in all populations and at all ages and has significant physical, psychosocial, and financial consequences.
Journal ArticleDOI
The Novel Zinc Finger-Containing Transcription Factor Osterix Is Required for Osteoblast Differentiation and Bone Formation
Kazuhisa Nakashima,Xin Zhou,Gary R. Kunkel,Zhaoping Zhang,Jian Min Deng,Richard R. Behringer,Benoit de Crombrugghe +6 more
TL;DR: It is proposed that Runx2/Cbfa1-expressing preosteoblasts are still bipotential cells, because Osx null preostEoblasts express typical chondrocyte marker genes, and Osx acts downstream of Runx 2/C bfa1.
Journal ArticleDOI
Functional interaction of beta-catenin with the transcription factor LEF-1.
Jürgen Behrens,von Kries Jp,Michael Kühl,Bruhn L,Bruhn L,Doris Wedlich,Rudolf Grosschedl,Rudolf Grosschedl,Walter Birchmeier +8 more
TL;DR: β-catenin regulates gene expression by direct interaction with transcription factors such as LEF-1, providing a molecular mechanism for the transmission of signals from cell-adhesion components or wnt protein to the nucleus.
Journal ArticleDOI
LDL Receptor-Related Protein 5 (LRP5) Affects Bone Accrual and Eye Development
Yaoqin Gong,R. B. Slee,Naomi Fukai,Georges Rawadi,Sergio Roman-Roman,Anthony M. Reginato,H. W. Wang,Tim Cundy,Francis H. Glorieux,Dorit Lev,M. Zacharin,Konrad Oexle,Jose Marcelino,Wafaa M. Suwairi,Shauna Heeger,G. Sabatakos,Suneel S. Apte,W. N. Adkins,J. Allgrove,M. Arslan-Kirchner,J. A. Batch,Peter Beighton,Graeme C.M. Black,R. G. Boles,L. M. Boon,C. Borrone,Han G. Brunner,G. F. Carle,Bruno Dallapiccola,A. De Paepe,B. Floege,M. L. Halfhide,Barbara Hall,Raoul C.M. Hennekam,Tatsuo Hirose,A. Jans,Harald Jüppner,Chong Ae Kim,K. Keppler-Noreuil,A. Kohlschuetter,Didier Lacombe,M. Lambert,E. Lemyre,T. Letteboer,Leena Peltonen,Rajkumar Ramesar,M. Romanengo,H. Somer,E. Steichen-Gersdorf,Beat Steinmann,Beth A. Sullivan,Andrea Superti-Furga,W. Swoboda,M. J. van den Boogaard,W. Van Hul,Miikka Vikkula,Marcela Votruba,Bernhard Zabel,Teresa Garcia,Roland Baron,Bjorn R. Olsen,Matthew L. Warman +61 more
TL;DR: It is reported that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth and is important for the establishment of peak bone mass.
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