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Calcified Tissue International

, Volume 100, Issue 1, pp 67–79 | Cite as

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

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

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.

Keywords

Glucocorticoid Osteoporosis Bone loss LLP2A-Ale Angiogenesis 

Notes

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).

Compliance with Ethical Standards

Conflict of interest

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.

Supplementary material

223_2016_195_MOESM1_ESM.docx (28 kb)
Supplementary material 1 (DOCX 28 kb)

References

  1. 1.
    Weinstein RS (2012) Glucocorticoid-induced osteoporosis and osteonecrosis. Endocrinol Metab Clin North Am 41:595–611CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    LoCascio V, Bonucci E, Imbimbo B et al (1990) Bone loss in response to long-term glucocorticoid therapy. Bone Miner 8:39–51CrossRefPubMedGoogle Scholar
  3. 3.
    Angeli A, Guglielmi G, Dovio A et al (2006) High prevalence of asymptomatic vertebral fractures in post-menopausal women receiving chronic glucocorticoid therapy: a cross-sectional outpatient study. Bone 39:253–259CrossRefPubMedGoogle Scholar
  4. 4.
    Steinbuch M, Youket TE, Cohen S (2004) Oral glucocorticoid use is associated with an increased risk of fracture. Osteoporos Int: J Establ Result Coop Between Eur Found Osteoporos Nat Osteoporos Found USA 15:323–328CrossRefGoogle Scholar
  5. 5.
    Abu EO, Horner A, Kusec V et al (2000) The localization of the functional glucocorticoid receptor alpha in human bone. J Clin Endocrinol Metab 85:883–889PubMedGoogle Scholar
  6. 6.
    Weinstein RS, Jilka RL, Parfitt AM et al (1998) Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Investig 102:274–282CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Cui Q, Wang GJ, Balian G (2000) Pluripotential marrow cells produce adipocytes when transplanted into steroid-treated mice. Connect Tissue Res 41:45–56CrossRefPubMedGoogle Scholar
  8. 8.
    Weinstein RS (2010) Glucocorticoids, osteocytes, and skeletal fragility: the role of bone vascularity. Bone 46:564–570CrossRefPubMedGoogle Scholar
  9. 9.
    Ono N, Ono W, Nagasawa T et al (2014) A subset of chondrogenic cells provides early mesenchymal progenitors in growing bones. Nat Cell Biol 16:1157–1167CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Park J, Gebhardt M, Golovchenko S et al (2015) Dual pathways to endochondral osteoblasts: a novel chondrocyte-derived osteoprogenitor cell identified in hypertrophic cartilage. Biol Open 4:608–621CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Hartmann K, Koenen M, Schauer S et al (2016) Molecular actions of glucocorticoids in cartilage and bone during health, disease, and steroid therapy. Physiol Rev 96:409–447CrossRefPubMedGoogle Scholar
  12. 12.
    Janke LJ, Liu C, Vogel P et al (2013) Primary epiphyseal arteriopathy in a mouse model of steroid-induced osteonecrosis. Am J Pathol 183:19–25CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Lai KA, Shen WJ, Yang CY et al (2005) The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis. A randomized clinical study. J Bone Joint Surg Am 87:2155–2159PubMedGoogle Scholar
  14. 14.
    Whittier X, Saag KG (2016) Glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am 42:177–189CrossRefPubMedGoogle Scholar
  15. 15.
    Canalis E, Giustina A, Bilezikian JP (2007) Mechanisms of anabolic therapies for osteoporosis. N Engl J Med 357:905–916CrossRefPubMedGoogle Scholar
  16. 16.
    Saag KG, Zanchetta JR, Devogelaer JP et al (2009) Effects of teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: thirty-six-month results of a randomized, double-blind, controlled trial. Arthritis Rheum 60:3346–3355CrossRefPubMedGoogle Scholar
  17. 17.
    Weinstein RS, Jilka RL, Almeida M et al (2010) Intermittent parathyroid hormone administration counteracts the adverse effects of glucocorticoids on osteoblast and osteocyte viability, bone formation, and strength in mice. Endocrinology 151:2641–2649CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Kaufman JM, Lapauw B, Goemaere S (2014) Current and future treatments of osteoporosis in men. Best Pract Res Clin Endocrinol Metab 28:871–884CrossRefPubMedGoogle Scholar
  19. 19.
    Padhi D, Allison M, Kivitz AJ et al (2014) Multiple doses of sclerostin antibody romosozumab in healthy men and postmenopausal women with low bone mass: a randomized, double-blind, placebo-controlled study. J Clin Pharmacol 54:168–178CrossRefPubMedGoogle Scholar
  20. 20.
    McClung MR, Grauer A, Boonen S et al (2014) Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 370:412–420CrossRefPubMedGoogle Scholar
  21. 21.
    Achiou Z, Toumi H, Touvier J et al (2015) Sclerostin antibody and interval treadmill training effects in a rodent model of glucocorticoid-induced osteopenia. Bone 81:691–701CrossRefPubMedGoogle Scholar
  22. 22.
    Yao W, Dai W, Jiang L et al (2016) Sclerostin-antibody treatment of glucocorticoid-induced osteoporosis maintained bone mass and strength. Osteoporos Int: J Establ Result Coop Between Eur Found Osteoporos Nat Osteoporos Found USA 27:283–294CrossRefGoogle Scholar
  23. 23.
    Peng L, Liu R, Marik J et al (2006) Combinatorial chemistry identifies high-affinity peptidomimetics against α4β1 integrin for in vivo tumor imaging. Nat Chem Biol 2:381–389CrossRefPubMedGoogle Scholar
  24. 24.
    Guan M, Yao W, Liu R et al (2012) Directing mesenchymal stem cells to bone to augment bone formation and increase bone mass. Nat Med 18:456–462CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Herberg S, Hill WD (2012) Two birds with one bone? IBMS BoneKEy. 9:115. doi: 10.1038/bonekey.2012.115 CrossRefGoogle Scholar
  26. 26.
    Yao W, Lane NE (2015) Targeted delivery of mesenchymal stem cells to the bone. Bone 70:62–65CrossRefPubMedGoogle Scholar
  27. 27.
    Yao W, Guan M, Jia J et al (2013) Reversing bone loss by directing mesenchymal stem cells to bone. Stem Cells 31:2003–2014CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Yao W, Cheng Z, Busse C et al (2008) Glucocorticoid excess in mice results in early activation of osteoclastogenesis and adipogenesis and prolonged suppression of osteogenesis: a longitudinal study of gene expression in bone tissue from glucocorticoid-treated mice. Arthritis Rheum 58:1674–1686CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Dai W, Jiang L, Lay YA et al (2015) Prevention of glucocorticoid induced bone changes with beta-ecdysone. Bone 74:48–57CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Yao W, Cheng Z, Pham A et al (2008) Glucocorticoid-induced bone loss in mice can be reversed by the actions of parathyroid hormone and risedronate on different pathways for bone formation and mineralization. Arthritis Rheum 58:3485–3497CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lane NE, Yao W, Balooch M et al (2006) Glucocorticoid-treated mice have localized changes in trabecular bone material properties and osteocyte lacunar size that are not observed in placebo-treated or estrogen-deficient mice. J Bone Miner Res: Off J Am Soc Bone Miner Res 21:466–476CrossRefGoogle Scholar
  32. 32.
    Parfitt AM, Drezner MK, Glorieux FH et al (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res: Off J Am Soc Bone Miner Res 2:595–610CrossRefGoogle Scholar
  33. 33.
    Dempster DW, Compston JE, Drezner MK et al (2013) Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res: Off J Am Soc Bone Miner Res 28:2–17CrossRefGoogle Scholar
  34. 34.
    Turner CH, Burr DB (1993) Basic biomechanical measurements of bone: a tutorial. Bone 14:595–608CrossRefPubMedGoogle Scholar
  35. 35.
    Ansari B, Coates PJ, Greenstein BD et al (1993) In situ end-labelling detects DNA strand breaks in apoptosis and other physiological and pathological states. J Pathol 170:1–8CrossRefPubMedGoogle Scholar
  36. 36.
    Bouvard B, Gallois Y, Legrand E et al (2013) Glucocorticoids reduce alveolar and trabecular bone in mice. Joint Bone Spine: Revue Du Rhumatisme 80:77–81CrossRefGoogle Scholar
  37. 37.
    Jilka RL, Noble B, Weinstein RS (2013) Osteocyte apoptosis. Bone 54:264–271CrossRefPubMedGoogle Scholar
  38. 38.
    Saag KG, Emkey R, Schnitzer TJ et al (1998) Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group. N Engl J Med 339:292–299CrossRefPubMedGoogle Scholar
  39. 39.
    Adachi JD, Saag KG, Delmas PD et al (2001) Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial. Arthritis Rheum 44:202–211CrossRefPubMedGoogle Scholar
  40. 40.
    Cohen S, Levy RM, Keller M et al (1999) Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 42:2309–2318CrossRefPubMedGoogle Scholar
  41. 41.
    Reid DM, Hughes RA, Laan RF et al (2000) Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. European Corticosteroid-Induced Osteoporosis Treatment Study. J Bone Miner Res: Off J Am Soc Bone Miner Res 15:1006–1013CrossRefGoogle Scholar
  42. 42.
    Nyman JS, Roy A, Shen X et al (2006) The influence of water removal on the strength and toughness of cortical bone. J Biomech 39:931–938CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Wang G, Zhang CQ, Sun Y et al (2010) Changes in femoral head blood supply and vascular endothelial growth factor in rabbits with steroid-induced osteonecrosis. J Int Med Res 38:1060–1069CrossRefPubMedGoogle Scholar
  44. 44.
    Jiang Y, Liu C, Chen W et al (2015) Tetramethylpyrazine enhances vascularization and prevents osteonecrosis in steroid-treated rats. Biomed Res Int 2015:315850PubMedPubMedCentralGoogle Scholar
  45. 45.
    Watt SM, Gullo F, van der Garde M et al (2013) The angiogenic properties of mesenchymal stem/stromal cells and their therapeutic potential. Br Med Bull 108:25–53CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Phinney DG (2007) Biochemical heterogeneity of mesenchymal stem cell populations: clues to their therapeutic efficacy. Cell Cycle 6:2884–2889CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Geetha Mohan
    • 1
  • Evan Yu-An Lay
    • 1
  • Haley Berka
    • 1
  • Lorna Ringwood
    • 1
  • Alexander Kot
    • 1
  • Haiyan Chen
    • 1
  • Wei Yao
    • 1
  • Nancy E. Lane
    • 1
  1. 1.Center for Musculoskeletal HealthUniversity of California at Davis School of MedicineSacramentoUSA

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