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A Novel Hybrid Compound LLP2A-Ale Both Prevented and Rescued the Osteoporotic Phenotype in a Mouse Model of Glucocorticoid-Induced Osteoporosis

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Abstract

Prolonged glucocorticoid (GC) administration causes secondary osteoporosis (GIOP) and non-traumatic osteonecrosis. LLP2A-Ale is a novel bone-seeking compound that recruits mesenchymal stem cells to the bone surface, stimulates bone formation, and increases bone mass. The purpose of this study was to determine if treatment with LLP2A-Ale alone or in combination with parathyroid hormone (PTH) could prevent or treat GIOP in a mouse model. Four-month-old male Swiss-Webster mice were randomized to a prevention study with placebo, GC (day 1–28), and GC + LLP2A-Ale (IV, day 1) or a treatment study with placebo, GC (days 1–56), GC + LLP2A-Ale (IV, day 28), GC + PTH, and GC + LLP2A-Ale + PTH (days 28–56). Mice were killed on day 28 (prevention study) or on day 56 (treatment study). The study endpoints included bone mass, bone strength, serum markers of bone turnover (P1NP and CTX-I) and angiogenesis (VEGF-A), surface-based bone turnover, and blood vessel density. LLP2A-Ale prevented GC-induced bone loss and increased mechanical strength in the vertebral body (days 28 and 56) and femur (day 56). LLP2A-Ale, PTH, and LLP2A-Ale + PTH treatment significantly increased the mineralizing surface, bone formation rate, mineral apposition rate, double-labeled surface, and serum P1NP level on day 56. LLP2A-Ale and PTH treatment increased femoral blood vessel density and LLP2A-Ale increased serum VEGF-A on day 28. Therefore, LLP2A-Ale monotherapy could be a potential option to both prevent and treat GC-induced osteoporosis and bone fragility.

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Acknowledgments

This work was supported by National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS), Grant Numbers: P50AR060752, P50AR063043, R01 AR043052, R01 AR061366, and the California Institute of Regenerative Medicine (CIRM).

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  1. Center for Musculoskeletal Health, University of California at Davis School of Medicine, 4625 2nd Avenue, Suite 2006, Sacramento, CA, 95817, USA

    Geetha Mohan, Evan Yu-An Lay, Haley Berka, Lorna Ringwood, Alexander Kot, Haiyan Chen, Wei Yao & Nancy E. Lane

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  1. Geetha Mohan
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Correspondence to Nancy E. Lane.

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Geetha Mohan, Evan Yu-An Lay, Haley Berka, Lorna Ringwood, Alexander Kot, Haiyan Chen, Wei Yao, and Nancy E Lane declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This study only reports data from animal experiments for which we have included the statement on animal welfare. We do not have any patient data or individual participants in this study.

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Mohan, G., Lay, E.YA., Berka, H. et al. A Novel Hybrid Compound LLP2A-Ale Both Prevented and Rescued the Osteoporotic Phenotype in a Mouse Model of Glucocorticoid-Induced Osteoporosis. Calcif Tissue Int 100, 67–79 (2017). https://doi.org/10.1007/s00223-016-0195-6

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