Sclerostin-antibody treatment of glucocorticoid-in
來源：本站 時(shí)間：2017-03-23 00:00:00
Abstract
Summary This study was to determine if antibody against
sclerostin (Scl-Ab) could prevent glucocorticoid (GC)-induced
osteoporosis in mice. We found that Scl-Ab prevented
GC-induced reduction in bone mass and bone strength and
that the anabolic effects of Scl-Ab might be partially achieved
through the preservation of osteoblast activity through
autophagy.
Introduction Glucocorticoids (GCs) inhibit bone formation
by altering osteoblast and osteocyte cell activity and lifespan.
A monoclonal antibody against sclerostin, Scl-Ab, increased
bone mass in both preclinical animal and clinical studies in
subjects with low bone mass. The objectives of this study
were to determine if treatment with the Scl-Ab could prevent
loss of bone mass and strength in a mouse model of GC excess
and to elucidate if Scl-Ab modulated bone cell activity
through autophagy.
Methods We generated reporter mice that globally expressed
dsRed fused to LC3, a protein marker for autophagosomes,
and evaluated the dose-dependent effects of GCs (0, 0.8, 2.8,
and 4 mg/kg/day) and Scl-Ab on autophagic osteoblasts, bone
mass, and bone strength.
Results GC treatment at 2.8 and 4 mg/kg/day of methylprednisolone
significantly lowered trabecular bone volume (Tb-
BV/TV) at the lumbar vertebrae and distal femurs, cortical
bone mass at the mid-shaft femur (FS), and cortical bone
strength compared to placebo (PL). In mice treated with GC
and Scl-Ab, Tb-BV/TV increased by 60–125 %, apparent
bone strength of the lumbar vertebrae by 30–70 %, FS-BV
by 10–18 %, and FS-apparent strength by 13–15 %, as compared
to GC vehicle-treated mice. GC treatment at 4 mg/kg/
day reduced the number of autophagic osteoblasts by 70% on
the vertebral trabecular bone surface compared to the placebo
group (PL, GC 0 mg), and GC + Scl-Ab treatment.
Conclusions Treatment with Scl-Ab prevented GC-induced reduction
in both trabecular and cortical bone mass and strength
and appeared tomaintain osteoblast activity through autophagy.
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