Sclerostin antibody increases bone mass by stimulating bone formation and inhibiting bone resorption in a hindlimb-immobilization rat model
Research Highlights
► Immobilization decreased bone formation and increased bone resorption in rats. ►Sclerostin inhibition increased trabecular, endocortical and periosteal bone formation in immobilized tibia. ► The effect of Scl-Ab on trabecular bone in immobilized tibia appears to be less dramatic than that in normal-loaded tibia.
Introduction
Sclerostin deficiency in humans, together with data from sclerostin-knockout mice, suggests that sclerostin inhibition might be an attractive approach for the development of a novel bone anabolic agent [1], [2], [3], [4]. Studies have demonstrated that inhibition of sclerostin by a sclerostin monoclonal antibody (Scl-Ab) stimulated bone formation, and increased bone mass and bone strength in the ovariectomy-induced bone loss rat [5] and gonad-intact female monkey models [6]. Dose-dependent increases in biochemical markers of bone formation and decreases in a bone resorption marker were observed following a single subcutaneous injection of Scl-Ab in healthy post-menopausal women [7]. However, it has yet to be demonstrated whether Scl-Ab can build bone in the setting of the immobilized/disuse-induced osteopenia that occurs in paraplegic conditions, space flight and prolonged bed rest. It has been reported that increases in loading of bone were associated with decreased sclerostin expression [8] and bone loss did not occur after unloading in mice lacking sclerostin [4]. In the current study, we employed the modified Swedish adult rat right hindlimb-immobilization model [9], [10], [11], [12] to test the effects of Scl-Ab on the under-loaded (UL) bone. A group of normal-loaded rats were also treated with Scl-Ab as a reference for the effects of Scl-Ab on normal-loaded bone in these adult female rats.
Section snippets
Materials and methods
The Institutional Animal Care and Use Committee at the University of Utah approved all animal procedures in this study.
Results
At the end of the study, body weights in UL rats were 15% less than those of NL rats regardless of treatment. Both doses of the Scl-Ab had no effect on body weight (data not shown).
Muscle weights in UL rats were significantly lower as compared with basal controls and NL controls. Specifically, the right soleus, gastrocnemius and quadriceps muscles weighed 44%, 59% and 56% less, respectively, relative to beginning controls. Treatment with 5 or 25 mg/kg Scl-Ab had no effect on muscle weight in
Discussion
We studied antibody-mediated sclerostin inhibition in adult female rats with or without right hindlimb-immobilization. Scl-Ab treatment significantly induced increases in trabecular and cortical bone under both normal-loaded and under-loaded conditions. The increased bone mass with Scl-Ab treatment was due to increased bone formation and decreased bone resorption on both trabecular and endocortical bone surfaces, as well as increased bone formation on periosteal surfaces. Furthermore,
Conflict of interest
Tian and Jee have no conflict of interest. Li, Paszty and Ke have corporate appointments with Amgen, Inc.
Acknowledgments
The authors acknowledge the support of Rebecca B. Setterberg and Min Chen for their excellent technical assistance. The funding for this study was supported by Amgen Inc. and UCB. The authors thank all members of the Amgen and UCB (Slough, United Kingdom) sclerostin team for their support of this study.
References (28)
- et al.
Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin
J Biol Chem
(2008) - et al.
Long-term anabolic effects of prostaglandin-E2 on tibial diaphyseal bone in male rats
Bone Miner
(1991) Sclerosteosis
J Med Genet
(1988)- et al.
The natural history of sclerosteosis
Clin Genet
(2003) - et al.
Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength
J Bone Miner Res
(2008) - et al.
Sclerostin mediates bone response to mechanical loading through anatogonizing Wnt/B-catenin signaling
J Bone Miner Res
(2009) - et al.
Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis
J Bone Miner Res
(2009) - et al.
Two doses of sclerostin antibody in cynomolgus monkeys increases bone formation, bone mineral density, and bone strength
J Bone Miner Res
(2010) - et al.
Anti-sclerostin antibody increases markers of bone formation in healthy postmenopausal women
J Bone Miner Res
(2007) The effect of thyroparathyroidectomy: development of disuse osteoporosis in adult rats
Clin Orthop Relat Res
(1976)
Adaptation of cancellous bone to aging and immobilization in the rat. A single photon absorptiometry and histomorphometry study
Anat Rec
Adaptation of diaphyseal structure to aging and decreased mechanical loading in adult rats: a densitometric and histomorphometry study
Anat Rec
Adaptation of cancellous bone to overloading in the adult rat: a single photon absorptiometry study
Anat Rec
Relationship between surface, area and thickness of iliac trabecular bone in aging and in osteoporosis. Implications for the micronatomic and cellular mechanisms of bone loss
J Clin Invest
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