RRC ID 37653
Author Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, Gao Y, Shalhoub V, Tipton B, Haldankar R, Chen Q, Winters A, Boone T, Geng Z, Niu QT, Ke HZ, Kostenuik PJ, Simonet WS, Lacey DL, Paszty C.
Title Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis.
Journal J Bone Miner Res
Abstract The development of bone-rebuilding anabolic agents for potential use in the treatment of bone loss conditions, such as osteoporosis, has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation, although the magnitude and extent of sclerostin's role in the control of bone formation in the aging skeleton is still unclear. To study this unexplored area of sclerostin biology and to assess the pharmacologic effects of sclerostin inhibition, we used a cell culture model of bone formation to identify a sclerostin neutralizing monoclonal antibody (Scl-AbII) for testing in an aged ovariectomized rat model of postmenopausal osteoporosis. Six-month-old female rats were ovariectomized and left untreated for 1 yr to allow for significant estrogen deficiency-induced bone loss, at which point Scl-AbII was administered for 5 wk. Scl-AbII treatment in these animals had robust anabolic effects, with marked increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. This not only resulted in complete reversal, at several skeletal sites, of the 1 yr of estrogen deficiency-induced bone loss, but also further increased bone mass and bone strength to levels greater than those found in non-ovariectomized control rats. Taken together, these preclinical results establish sclerostin's role as a pivotal negative regulator of bone formation in the aging skeleton and, furthermore, suggest that antibody-mediated inhibition of sclerostin represents a promising new therapeutic approach for the anabolic treatment of bone-related disorders, such as postmenopausal osteoporosis.
Volume 24(4)
Pages 578-88
Published 2009-4-1
DOI 10.1359/jbmr.081206
PMID 19049336
MeSH Animals Antibodies, Monoclonal / pharmacology* Antibodies, Monoclonal / therapeutic use* Biological Assay Biomechanical Phenomena Bone Density / drug effects Bone Morphogenetic Proteins / immunology* Bone and Bones / drug effects* Bone and Bones / pathology Cell Lineage / drug effects Disease Models, Animal Female Femur / drug effects Femur / pathology Genetic Markers / immunology* Humans Lumbar Vertebrae / drug effects Lumbar Vertebrae / pathology Mice Neutralization Tests Organ Size / drug effects Osteoblasts / cytology Osteoblasts / drug effects Osteocalcin / blood Osteogenesis / drug effects* Osteoporosis, Postmenopausal / blood Osteoporosis, Postmenopausal / drug therapy* Osteoporosis, Postmenopausal / pathology Osteoporosis, Postmenopausal / physiopathology Ovariectomy Rats Rats, Sprague-Dawley Tibia / drug effects Tibia / pathology Tomography, X-Ray Computed
IF 5.854
Times Cited 530
Human and Animal Cells MC3T3-E1(RCB1126)