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

Wei Yao, W. Dai, L. Jiang, E. Y.A. Lay, Z. Zhong, R. O. Ritchie, X. Li, H. Ke, Nancy E Lane

Research output: Contribution to journalArticle

51 Citations (Scopus)

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.

Original languageEnglish (US)
JournalOsteoporosis International
DOIs
StateAccepted/In press - Sep 18 2015

Fingerprint

Glucocorticoids
Osteoporosis
Bone and Bones
Antibodies
Osteoblasts
Autophagy
Therapeutics
Lumbar Vertebrae
Placebos
Femur
Anabolic Agents
Osteocytes
Methylprednisolone
Osteogenesis
Monoclonal Antibodies

Keywords

  • Autophagy
  • dsRed-LC3 mouse
  • Glucocorticoid-induced osteoporosis
  • Osteoblast
  • Sclerostin-antibody

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism

Cite this

Sclerostin-antibody treatment of glucocorticoid-induced osteoporosis maintained bone mass and strength. / Yao, Wei; Dai, W.; Jiang, L.; Lay, E. Y.A.; Zhong, Z.; Ritchie, R. O.; Li, X.; Ke, H.; Lane, Nancy E.

In: Osteoporosis International, 18.09.2015.

Research output: Contribution to journalArticle

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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.",
keywords = "Autophagy, dsRed-LC3 mouse, Glucocorticoid-induced osteoporosis, Osteoblast, Sclerostin-antibody",
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T1 - Sclerostin-antibody treatment of glucocorticoid-induced osteoporosis maintained bone mass and strength

AU - Yao, Wei

AU - Dai, W.

AU - Jiang, L.

AU - Lay, E. Y.A.

AU - Zhong, Z.

AU - Ritchie, R. O.

AU - Li, X.

AU - Ke, H.

AU - Lane, Nancy E

PY - 2015/9/18

Y1 - 2015/9/18

N2 - 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.

AB - 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.

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KW - Osteoblast

KW - Sclerostin-antibody

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