Abstract
Sclerostin knock-out mice or sclerostin antibody (Scl-Ab) treated wild-type mice displayed decreased marrow adiposity. But the effects of Scl-Ab on estrogen deficiency-induced marrow fat expansion remain elusive. In this work, 45 female New Zealand rabbits were equally divided into sham-operation, ovariectomy controls, and ovariectomy treated with Scl-Ab for 5 months. MR spectroscopy was performed to longitudinally assess marrow fat fraction at baseline conditions, 2.5 and 5 months post-operatively, respectively. We evaluated bone mineral density (BMD), bone structural parameters, serum bone biomarkers, and quantitative parameters of marrow adipocytes. Ovariectomized rabbits markedly exhibited expansion of marrow fat in a time-dependent manner, with a variation of marrow fat fraction (+17.8%) at 2.5 months relative to baseline and it was maintained until 5 months (+30.4%, all P < 0.001), which was accompanied by diminished BMD and deterioration of trabecular microstructure. Compared to sham controls, adipocyte mean diameter, adipocyte density and adipocytes area percentage was increased by 42.9, 68.3, and 108.6% in ovariectomized rabbits, respectively. Scl-Ab treatment increased serum bone formation marker and alleviated the ovariectomy escalation of serum bone resorption marker. It remarkably lessened the ovariectomy-mediated deterioration of BMD, and morphometric characteristics of trabecular bone. Marrow fat fraction was decreased significantly with Scl-Ab to levels matching that of sham-operated controls and correlated positively with reductions in adipocyte mean diameter, percentage adipocyte volume per marrow volume, and adipocyte density. Taken together, early Scl-Ab treatment reverts marrow fat expansion seen in ovariectomized rabbits in addition to having a beneficial effect on bone mass and microstructural properties.
Highlights
Osteoporosis remains largely underdiagnosed and undertreated, even after the first fracture has occurred
Due to progresses in understanding the mechanisms and the causes of bone fragility, novel and promising therapeutic targets for osteoporosis have been identified [2]. Studies in both animal models and human of sclerosteosis and van Buchem disease have demonstrated that sclerostin plays an important role in regulating bone metabolism [3,4,5]
Data are expressed as mean ± SD. aP < 0.05 comparison with the sham controls and bP < 0.05 comparison with the OVX controls analyzed by one-way analysis of variance (ANOVA) with the Bonferroni posthoc test
Summary
Osteoporosis remains largely underdiagnosed and undertreated, even after the first fracture has occurred. Due to progresses in understanding the mechanisms and the causes of bone fragility, novel and promising therapeutic targets for osteoporosis have been identified [2]. Studies in both animal models and human of sclerosteosis and van Buchem disease have demonstrated that sclerostin plays an important role in regulating bone metabolism [3,4,5]. Sclerosteosis and van Buchem disease result in generalized high bone mass due to overactive osteoblast activity [6, 7]. Previous studies demonstrated that estrogen-deficient women had higher sclerostin serum levels [9], and high serum levels of sclerostin were associated with increased fracture risk, in populations with lower bone mass [10]. The exact source of sclerostin within the bone marrow microenvironment under pathophysiologic conditions, the mechanisms by which sclerostin regulates the activity of osteoblasts and osteoclasts, and its autocrine effects on osteocytes remain elusive [11, 12]
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