Sclerostin-antibody treatment of glucocorticoid-induced osteoporosis maintained bone mass and strength

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 to maintain osteoblast activity through autophagy.

Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin

“…(10) Consistent with our current findings in skeletally mature Sost/ sclerostin-deficient mice, previous studies showed that pharmacologic inhibition of sclerostin with a neutralizing antibody opposed the lack of bone gain and the loss of strength induced by glucocorticoids in growing mice. (51,52) Although it was proposed that these effects were due to preservation of Journal of Bone and Mineral Research osteoblast activity, (52) mice treated with glucocorticoids and the anti-sclerostin antibody in these earlier studies exhibited lower circulating TRAP5b (51) or CTX-1, (52) but still markedly reduced bone formation markers osteocalcin and P1NP, (51) compared to the corresponding mice treated with glucocorticoids alone. Likewise, our in vivo studies show that sustained activation of the Wnt/b-catenin signaling in Sost-deficient mice abolishes the increase in resorption induced by glucocorticoids but not the decreased bone formation.…”

Osteoporosis and autophagy: What is the relationship?

“…74,87 Administration of an antibody against sclerostin, an inhibitor of bone formation by osteoblasts, was able to prevent bone loss promoted by treatment with glucocorticoids in male mice. 88 In the study, treatment with high doses of glucocorticoids reduced the percentage of LC3-positive osteoblasts, an autophagic marker, thus reducing the viability of these cells and causing bone loss. Treatment with anti-sclerostin antibody, in turn, maintained the viability of osteoblasts by increasing autophagy in these cells and reducing bone loss caused by glucocorticoid treatment.…”

“…Treatment with anti-sclerostin antibody, in turn, maintained the viability of osteoblasts by increasing autophagy in these cells and reducing bone loss caused by glucocorticoid treatment. 88 However, further studies are needed to understand the specific mechanisms by which sclerostin, or its antibody, regulates the autophagic pathway in bone cells.…”

Animal models to explore the effects of glucocorticoids on skeletal growth and structure

“…In cultured human osteoblasts, exogenous GC administration also results in the suppression of the canonical Wnt-β-catenin signalling pathway, which prevents osteoblast apoptosis and encourages progression through the osteoblast cell cycle and thus proliferation (Ohnaka et al 2005). Furthermore, murine GC exposure has been shown to upregulate sclerostin gene expression, which antagonises Wnt stimulation of osteoblast differentiation (Yao et al 2016). Using a transgenic mouse line, GCs have also been shown to suppress interleukin 11 expression, which further inhibits osteoblast differentiation (Rauch et al 2010).…”

“…In addition, it is not yet clear whether genomic or non-genomic pathways play the major role in GIO (Hartmann et al 2016). Altered bone structure was observed in two-month-old male mice treated with 15 mg/kg/day of corticosterone (Herrmann et al 2009), but only 2.8 mg/kg/day of methylprednisolone was needed to induce similar changes in mice of same age and sex (Yao et al 2016). Therefore, methylprednisolone appears to be more potent than corticosterone in osteoporosis induction.…”