Sclerostin and Dickkopf-1 as therapeutic targets in bone diseases.
The processes of bone growth, modeling, and remodeling determine the structure, mass, and biomechanical properties of the skeleton. Dysregulated bone resorption or bone formation may lead to metabolic bone diseases. The Wnt pathway plays an important role in bone formation and regeneration, and expression of two Wnt pathway inhibitors, sclerostin and Dickkopf-1 (DKK1), appears to be associated with changes in bone mass. Inactivation of sclerostin leads to substantially increased bone mass in humans and in genetically manipulated animals. Studies in various animal models of bone disease have shown that inhibition of sclerostin using a monoclonal antibody (Scl-Ab) increases bone formation, density, and strength. Additional studies show that Scl-Ab improves bone healing in models of bone repair. Inhibition of DKK1 by monoclonal antibody (DKK1-Ab) stimulates bone formation in younger animals and to a lesser extent in adult animals and enhances fracture healing. Thus, sclerostin and DKK1 are emerging as the leading new targets for anabolic therapies to treat bone diseases such as osteoporosis and for bone repair. Clinical trials are ongoing to evaluate the effects of Scl-Ab and DKK1-Ab in humans for the treatment of bone loss and for bone repair.
Metabolic Disorders Research, Amgen Inc., One Amgen Center Drive, MS 29-M-B, Thousand Oaks, California 91320, USA. hke@amgen.com
Hua Zhu
HZ
Ke
William G
WG
Richards
Xiaodong
X
Li
Michael S
MS
Ominsky
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015519:Bone Density / Q000502:physiology; D001851:Bone Diseases, Metabolic / Q000188:drug therapy* / Q000503:physiopathology*; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D001862:Bone Resorption / Q000503:physiopathology; D005786:Gene Expression Regulation; D005819:Genetic Markers / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D010012:Osteogenesis / Q000502:physiology; D051381:Rats; D060449:Wnt Signaling Pathway / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D019485:Bone Morphogenetic Proteins; C501126:DKK1 protein, human; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; C422903:SOST protein, human