| RRC ID |
37653
|
| 著者 |
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.
|
| タイトル |
Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis.
|
| ジャーナル |
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.
|
| 巻・号 |
24(4)
|
| ページ |
578-88
|
| 公開日 |
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
|
| 引用数 |
530
|
|
WOS 分野
|
ENDOCRINOLOGY & METABOLISM
|
| リソース情報 |
| ヒト・動物細胞 |
MC3T3-E1(RCB1126) |
