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Early Response of Bone Marrow Osteoprogenitors to Skeletal Unloading and Sclerostin Antibody

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Abstract

Sclerostin functions as an antagonist to Wnt signaling and inhibits bone-forming activity. We studied the effects of skeletal unloading and treatment with sclerostin antibody (Scl-Ab) on mesenchymal stem cell, osteoprogenitor and osteoclast precursor pools, and their relationship to bone formation and resorption. Male C57BL/6 mice (5-months-old) were hind limb unloaded for 1 week or allowed normal ambulation and treated with Scl-Ab (25 mg/kg, s.c. injections on days 1 and 4) or placebo. Unloading decreased the serum concentration of bone formation marker P1NP (−35 %), number of colony-forming units (CFU) (−38 %), alkaline phosphatase–positive CFUs (CFU-AP+) (−51 %), and calcified nodules (−35 %); and resulted in a fourfold increase in the number of osteoclast precursors. The effects of Scl-Ab treatment on unloaded and normally loaded mice were nearly identical; Scl-Ab increased serum P1NP and the number of CFU, CFU-AP+, and calcified nodules in ex vivo cultures; and increased osteoblast and bone mineralizing surfaces in vivo. Although the marrow-derived osteoclast precursor population increased with Scl-Ab, the bone osteoclast surface did not change, and the serum concentration of osteoclast activity marker TRACP5b decreased. Our data suggest that short-term Scl-Ab treatment can prevent the decrease in osteoprogenitor population associated with skeletal unloading and increase osteoblast surface and bone mineralizing surface in unloaded animals. The anabolic effects of Scl-Ab treatment on bone are preserved during skeletal unloading. These findings suggest that Scl-Ab treatment can both increase bone formation and decrease bone resorption, and provide a new means for prevention and treatment of disuse osteoporosis.

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Acknowledgments

This work was supported by the Veterans Affairs Merit Review program, NASA, and the Northern California Institute for Research and Education.

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Authors and Affiliations

  1. Division of Endocrinology, Veterans Affairs Medical Center, University of California, San Francisco, CA, 94121, USA

    Mohammad Shahnazari, Vivian Chu & Bernard Halloran

  2. Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32610-0125, USA

    Thomas Wronski, Alyssa Williams & Alicia Leeper

  3. Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320, USA

    Marina Stolina & Hua Zhu Ke

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  1. Mohammad Shahnazari
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  2. Thomas Wronski
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  3. Vivian Chu
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  4. Alyssa Williams
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Correspondence to Bernard Halloran.

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Thomas Wronski received research funding from Amgen Inc. Marina Stolina and Hua Zhu Ke are employed by Amgen. Marina Stolina, Hua Zhu Ke, and Thomas Wronski have stock ownership in Amgen. Other authors have stated that they have no conflict of interest.

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Shahnazari, M., Wronski, T., Chu, V. et al. Early Response of Bone Marrow Osteoprogenitors to Skeletal Unloading and Sclerostin Antibody. Calcif Tissue Int 91, 50–58 (2012). https://doi.org/10.1007/s00223-012-9610-9

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