Osteocyte control of bone formation via sclerostin, a novel BMP antagonist.
There is an unmet medical need for anabolic treatments to restore lost bone. Human genetic bone disorders provide insight into bone regulatory processes. Sclerosteosis is a disease typified by high bone mass due to the loss of SOST expression. Sclerostin, the SOST gene protein product, competed with the type I and type II bone morphogenetic protein (BMP) receptors for binding to BMPs, decreased BMP signaling and suppressed mineralization of osteoblastic cells. SOST expression was detected in cultured osteoblasts and in mineralizing areas of the skeleton, but not in osteoclasts. Strong expression in osteocytes suggested that sclerostin expressed by these central regulatory cells mediates bone homeostasis. Transgenic mice overexpressing SOST exhibited low bone mass and decreased bone strength as the result of a significant reduction in osteoblast activity and subsequently, bone formation. Modulation of this osteocyte-derived negative signal is therapeutically relevant for disorders associated with bone loss.
Winkler
David G
DG
Department of Gene Function and Target Validation, Celltech R&D, Inc., Bothell, WA 98021, USA.
Sutherland
May Kung
MK
Geoghegan
James C
JC
Yu
Changpu
C
Hayes
Trenton
T
Skonier
John E
JE
Shpektor
Diana
D
Jonas
Mechtild
M
Kovacevich
Brian R
BR
Staehling-Hampton
Karen
K
Appleby
Mark
M
Brunkow
Mary E
ME
Latham
John A
JA
D048868:Adaptor Proteins, Signal Transducing; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D015519:Bone Density; D001846:Bone Development / Q000502:physiology*; D001851:Bone Diseases, Metabolic / Q000235:genetics; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D002460:Cell Line; D003001:Cloning, Molecular; D017931:DNA Primers; D005819:Genetic Markers / Q000235:genetics / Q000502:physiology*; D006023:Glycoproteins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007700:Kinetics; D008648:Mesoderm / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D010011:Osteocytes / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D048868:Adaptor Proteins, Signal Transducing; C525816:BMP6 protein, human; C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D017931:DNA Primers; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; C422903:SOST protein, human; C486030:Sost protein, mouse; D000469:Alkaline Phosphatase