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Continuous Treatment with a Low-Dose β-Agonist Reduces Bone Mass by Increasing Bone Resorption Without Suppressing Bone Formation

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Abstract

The sympathetic nervous system regulates bone remodeling through the β-adrenergic receptor (β-AR). However, the systemic roles of adrenergic actions on bone remodeling through the β-AR are largely unknown. In this study, we examined the dose effect of continuous treatment with isoprenaline, a nonspecific β-AR agonist, on bone remodeling. Male C57BL/6J mice were intrasubcutaneously administrated with four different doses (5, 25, 50, or 100 μg/g daily) of isoprenaline or vehicle using an osmotic pump for 2 weeks. The region of high-turnover cancellous bone was analyzed by microcomputed tomography (μCT). Continuous isoprenaline treatment caused a ~35.7% decline in the femoral cancellous bone volume fraction (BV/TV) at all doses (5–100 μg/g daily). Furthermore, continuous isoprenaline treatment weakened the bone mechanical properties in the trunk of lumbar vertebra 4 (L4). These parameters did not show significant differences between doses. Histomorphometric analysis revealed that isoprenaline doses of 50 μg/g daily or less did not significantly inhibit bone formation parameters, such as bone formation rate (BFR) and mineral surface/bone surface (MS/BS). Only the highest dose (100 μg/g daily) of isoprenaline significantly inhibited BFR and MS/BS. On the other hand, osteoclast number/bone surface (Oc.N/BS) was enhanced approximately 2.4-fold and osteoclast surface/bone surface (Oc.S/BS) was increased 2.0-fold by all doses of continuous isoprenaline treatment. The osteoclast parameters plateaued at the lowest dose (5 μg/g daily) of continuous isoprenaline treatment. These results indicate that chronic stimulation of β-AR with low-dose agonist treatment induces bone loss mainly via enhanced bone resorption.

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References

  1. Moore RE, Smith CK, Bailey CS, Voelkel EF, Tashjian AH Jr (1993) Characterization of beta-adrenergic receptors on rat and human osteoblast-like cells and demonstration that beta-receptor agonists can stimulate bone resorption in organ culture. Bone Miner 23:301–315

    Article  CAS  PubMed  Google Scholar 

  2. Togari A, Arai M, Mizutani S, Mizutani S, Koshihara Y, Nagatsu T (1997) Expression of mRNAs for neuropeptide receptors and β-adrenergic receptors in human osteoblasts and human osteogenic sarcoma cells. Neurosci Lett 233:125–128

    Article  CAS  PubMed  Google Scholar 

  3. Kellenberger S, Muller K, Richener H, Bilbe G (1998) Formoterol and isoproterenol induce c-fos gene expression in osteoblast-like cells by activating beta2-adrenergic receptors. Bone 22:471–478

    Article  CAS  PubMed  Google Scholar 

  4. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G (2000) Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100:197–207

    Article  CAS  PubMed  Google Scholar 

  5. Takeda S, Karsenty G (2001) Central control of bone formation. J Bone Miner Metab 19:195–198

    Article  CAS  PubMed  Google Scholar 

  6. Takeuchi T, Tsuboi T, Arai M, Togari A (2001) Adrenergic stimulation of osteoclastogenesis mediated by expression of osteoclast differentiation factor in MC3T3-E1 osteoblast-like cells. Biochem Pharmacol 61:579–586

    Article  CAS  PubMed  Google Scholar 

  7. Togari A (2002) Adrenergic regulation of bone metabolism: possible involvement of sympathetic innervation of osteoblastic and osteoclastic cells. Microsc Res Tech 58:77–84

    Article  CAS  PubMed  Google Scholar 

  8. Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G (2002) Leptin regulates bone formation via the sympathetic nervous system. Cell 111:305–317

    Article  CAS  PubMed  Google Scholar 

  9. Kondo A, Togari A (2003) In vivo stimulation of sympathetic nervous system modulates osteoblastic activity in mouse calvaria. Am J Physiol Endocrinol Metab 285:E661–E667

    CAS  PubMed  Google Scholar 

  10. Arai M, Nagasawa T, Koshihara Y, Yamamoto S, Togari A (2003) Effects of beta-adrenergic agonists on bone resorbing activity in human osteoclast-like cells. Biochem Biophys Acta 1640:137–142

    Article  CAS  PubMed  Google Scholar 

  11. Elefteriou F, Takeda S, Ebihara K, Magre J, Patano N, Kim CA, Ogawa Y, Liu X, Ware SM, Craigen WJ, Robert JJ, Vinson C, Nakao K, Capeau J, Karsenty G (2004) Serum leptin level is a regulator of bone mass. Proc Natl Acad Sci USA 101:3258–3263

    Article  CAS  PubMed  Google Scholar 

  12. Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, Kondo H, Richards WG, Bannon TW, Noda M, Clement K, Vaisse C, Karsenty G (2005) Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434:514–520

    Article  CAS  PubMed  Google Scholar 

  13. Togari A, Arai M, Kondo A (2005) The role of the sympathetic nervous system in controlling bone metabolism. Expert Opin Ther Targets 9:931–940

    Article  CAS  PubMed  Google Scholar 

  14. Kondo H, Nifuji A, Takeda S, Ezura Y, Rittling SR, Denhardt DT, Nakashima K, Karsenty G, Noda M (2005) Unloading induces osteoblastic cell suppression and osteoclastic cell activation to lead to bone loss via sympathetic nervous system. J Biol Chem 280:30192–30200

    Article  CAS  PubMed  Google Scholar 

  15. Bonnet N, Brunet-Imbault B, Arlettaz A, Horcajada MN, Collomp K, Benhamou CL, Courteix D (2005) Alteration of trabecular bone under chronic beta 2 agonists treatment. Med Sci Sports Exerc 37:1493–1501

    Article  CAS  PubMed  Google Scholar 

  16. Bonnet N, Benhamou CL, Brunet-Imbault B, Arlettaz A, Horcajada MN, Richard O, Vico L, Collomp K, Courteix D (2005) Severe bone alterations under beta 2 agonist treatment: bone mass, microarchitecture and strength analyses in female rats. Bone 37:622–633

    Article  CAS  PubMed  Google Scholar 

  17. Togari A, Arai M (2008) Pharmacological topics of bone metabolism: the physiological function of the sympathetic nervous system in modulating bone resorption. J Pharmacol Sci 106:542–546

    Article  CAS  PubMed  Google Scholar 

  18. Bonnet N, Pierroz DD, Ferrari SL (2008) Adrenergic control of bone remodeling and its implications for the treatment of osteoporosis. J Musculoskelet Neuronal Interact 8:94–104

    CAS  PubMed  Google Scholar 

  19. Tetradis S, Pilbeam CC, Liu Y, Herschman HR, Kream BE (1997) Parathyroid hormone increases prostaglandin G/H synthase-2 transcription by a cyclic adenosine 3′, 5′-monophosphate-mediated pathway in murine osteoblastic MC3T3-E1 cells. Endocrinology 138:3594–3600

    Article  CAS  PubMed  Google Scholar 

  20. Swarthout JT, D’Alonzo RC, Selvamurugan N, Partridge NC (2002) Parathyroid hormone-dependent signaling pathways regulating genes in bone cells. Gene 282:1–17

    CAS  PubMed  Google Scholar 

  21. Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R (1993) Anabolic actions of parathyroid hormone on bone. Endocr Rev 14:690–709

    CAS  PubMed  Google Scholar 

  22. Uzawa T, Hori M, Ejiri S, Ozawa H (1995) Comparison of the effects of intermittent and continuous administration of human parathyroid hormone(1–34) on rat bone. Bone 16:477–484

    CAS  PubMed  Google Scholar 

  23. Kitahara K, Ishijima M, Rittling SR, Tsuji K, Kurosawa H, Nifuji A, Denhardt DT, Noda M (2003) Osteopontin deficiency induces parathyroid hormone enhancement of cortical bone formation. Endocrinology 144:2132–2140

    Article  CAS  PubMed  Google Scholar 

  24. Pierroz DD, Bianchi E, Manen D, Rizzoli R, Bouxsein ML, Ferrari SL (2005) Arrestins selectively regulate the inhibitory effects of adrenergic agonists on bone and fat. J Bone Miner Res 20 Suppl 1:SA397

    Google Scholar 

  25. Pierroz DD, Baldock P, Bouxsein ML, Ferrari SL (2006) Low cortical bone mass in mice lacking beta 1 and beta 2 adrenergic receptors is associated with low bone formation and circulating IGF-1. J Bone Miner Res 21 Suppl 1:S277

    Google Scholar 

  26. Pierroz DD, Muzzin P, Glatt V, Bouxsein ML, Rizzoli R, Ferrari SL (2004) β1β2-Adrenergic receptor KO mice have decreased total body and cortical bone mass despite increased trabecular number. J Bone Miner Res 19:S32

    Google Scholar 

  27. Susulic VS, Frederich RC, Lawitts J, Tozzo E, Kahn BB, Harper ME, Himms-Hagen J, Flier JS, Lowell BB (1995) Targeted disruption of the beta3-adrenergic receptor gene. J Biol Chem 270:29483–29492

    Article  CAS  PubMed  Google Scholar 

  28. Kurabayashi T, Tomita M, Matsushita H, Honda A, Takakuwa K, Tanaka K (2001) Effects of a beta3 adrenergic receptor agonist on bone and bone marrow adipocytes in the tibia and lumbar spine of the ovariectomized rat. Calcif Tissue Int 68:248–254

    Article  CAS  PubMed  Google Scholar 

  29. Minkowitz B, Boskey AL, Lane JM, Pearlman HS, Vigorita VJ (1991) Effects of propranolol on bone metabolism in the rat. J Orthop Res 9:869–875

    Article  CAS  PubMed  Google Scholar 

  30. Bonnet N, Laroche N, Vico L, Dolleans E, Benhamou CL, Courteix D (2006) Dose effects of propranolol on cancellous and cortical bone in ovariectomized adult rats. J Pharmacol Exp Ther 318:1118–1127

    Article  CAS  PubMed  Google Scholar 

  31. Bonnet N, Benhamou CL, Malaval L, Goncalves C, Vico L, Eder V, Pichon C, Courteix D (2008) Low dose beta-blocker prevents ovariectomy-induced bone loss in rats without affecting heart functions. J Cell Physiol 217:819–827

    Article  CAS  PubMed  Google Scholar 

  32. Tommasini SM, Morgan TG, van der Meulen MCh, Jepsen KJ (2005) Genetic variation in structure–function relationships for the inbred mouse lumbar vertebral body. J Bone Miner Res 20:817–827

    Article  PubMed  Google Scholar 

  33. Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 2:595–610

    Article  CAS  PubMed  Google Scholar 

  34. Bogoyevitch MA, Andersson MB, Gillespie-Brown J, Clerk A, Glennon PE, Fuller SJ, Sugden PH (1996) Adrenergic receptor stimulation of the mitogen-activated protein kinase cascade and cardiac hypertrophy. Biochem J 314:115–121

    CAS  PubMed  Google Scholar 

  35. Fan GC, Yuan Q, Song G, Wang Y, Chen G, Qian J, Zhou X, Lee YJ, Ashraf M, Kranias EG (2006) Small heat-shock protein Hsp20 attenuates ß-agonist-mediated cardiac remodeling through apoptosis signal-regulating kinase 1. Circ Res 99:1233–1242

    Article  CAS  PubMed  Google Scholar 

  36. NIH consensus development panel on osteoporosis prevention, diagnosis, and therapy (2001) Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785–795

    Article  Google Scholar 

  37. Sontag A, Krege JH (2010) First fractures among postmenopausal women with osteoporosis. J Bone Miner Metab 28:485–488

    Article  CAS  PubMed  Google Scholar 

  38. Aitken SJ, Landao-Bassonga E, Ralston SH, Idris AI (2009) Beta2-adrenoreceptor ligands regulate osteoclast differentiation in vitro by direct and indirect mechanisms. Arch Biochem Biophys 482:96–103

    Article  CAS  PubMed  Google Scholar 

  39. Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF, Garnero P, Bouxsein ML, Bilezikian JP, Rosen CJ (2003) The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 349:1207–1215

    Article  CAS  PubMed  Google Scholar 

  40. Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer RM (2003) The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 349:1216–1226

    Article  CAS  PubMed  Google Scholar 

  41. Nuntapornsak A, Wongdee K, Thongbunchoo J, Krishnamra N, Charoenphandhu N (2010) Changes in the mRNA expression of osteoblast-related genes in response to beta3-adrenergic agonist in UMR106 cells. Cell Biochem Funct 28:45–51

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by Grants-in-Aid for Scientific Research (20791366 to H. K. and 20592193 to A. T.) from the Japan Society for the Promotion of Science and by a Grant-in Aid from Strategic Research AGU-Platform Formation (2008–2012).

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  1. Department of Pharmacology, School of Dentistry, Aichi-Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, 464-8650, Japan

    Hisataka Kondo & Akifumi Togari

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  1. Hisataka Kondo
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  2. Akifumi Togari
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Correspondence to Akifumi Togari.

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Kondo, H., Togari, A. Continuous Treatment with a Low-Dose β-Agonist Reduces Bone Mass by Increasing Bone Resorption Without Suppressing Bone Formation. Calcif Tissue Int 88, 23–32 (2011). https://doi.org/10.1007/s00223-010-9421-9

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  • DOI: https://doi.org/10.1007/s00223-010-9421-9

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