Beta-1 adrenergic agonist treatment mitigates negative changes in cancellous bone microarchitecture and inhibits osteocyte apoptosis during disuse

Joshua M. Swift, Sibyl N. Swift, Matthew Allen, Susan A. Bloomfield

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The sympathetic nervous system (SNS) plays an important role in mediating bone remodeling. However, the exact role that beta-1 adrenergic receptors (beta1AR) have in this process has not been elucidated. We have previously demonstrated the ability of dobutamine (DOB), primarily a beta1AR agonist, to inhibit reductions in cancellous bone formation and mitigate disuse-induced loss of bone mass. The purpose of this study was to characterize the independent and combined effects of DOB and hindlimb unloading (HU) on cancellous bone microarchitecture, tissue-level bone cell activity, and osteocyte apoptosis. Male Sprague-Dawley rats, aged 6-mos, were assigned to either normal cage activity (CC) or HU (n= 18/group) for 28 days. Animals were administered either daily DOB (4 mg/kg BW/d) or an equal volume of saline (VEH) (n= 9/gp). Unloading resulted in significantly lower distal femur cancellous BV/TV (-33%), Tb.Th ( -11%), and Tb.N (-25%) compared to ambulatory controls (CC-VEH). DOB treatment during HU attenuated these changes in cancellous bone microarchitecture, resulting in greater BV/TV (+29%), Tb.Th (+7%), and Tb.N (+21%) vs. HU-VEH. Distal femur cancellous vBMD (+11%) and total BMC (+8%) were significantly greater in DOB- vs. VEH-treated unloaded rats. Administration of DOB during HU resulted in significantly greater osteoid surface (+158%) and osteoblast surface (+110%) vs. HU-VEH group. Furthermore, Oc.S/BS was significantly greater in HU-DOB (+55%) vs. CC-DOB group. DOB treatment during unloading fully restored bone formation, resulting in significantly greater bone formation rate (+200%) than in HU-VEH rats. HU resulted in an increased percentage of apoptotic cancellous osteocytes (+85%), reduced osteocyte number (-16%), lower percentage of occupied osteocytic lacunae (-30%) as compared to CC-VEH, these parameters were all normalized with DOB treatment. Altogether, these data indicate that beta1AR agonist treatment during disuse mitigates negative changes in cancellous bone microarchitecture and inhibits increases in osteocyte apoptosis.

Original languageEnglish (US)
Article numbere106904
JournalPLoS One
Volume9
Issue number9
DOIs
StatePublished - Sep 11 2014

Fingerprint

Adrenergic beta-1 Receptor Agonists
adrenergic agonists
Osteocytes
Hindlimb Suspension
Dobutamine
Unloading
Bone
apoptosis
bones
Apoptosis
bone formation
Osteogenesis
Therapeutics
Rats
femur
agonists
Bone and Bones
Femur
rats
Adrenergic beta-1 Receptors

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Beta-1 adrenergic agonist treatment mitigates negative changes in cancellous bone microarchitecture and inhibits osteocyte apoptosis during disuse. / Swift, Joshua M.; Swift, Sibyl N.; Allen, Matthew; Bloomfield, Susan A.

In: PLoS One, Vol. 9, No. 9, e106904, 11.09.2014.

Research output: Contribution to journalArticle

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abstract = "The sympathetic nervous system (SNS) plays an important role in mediating bone remodeling. However, the exact role that beta-1 adrenergic receptors (beta1AR) have in this process has not been elucidated. We have previously demonstrated the ability of dobutamine (DOB), primarily a beta1AR agonist, to inhibit reductions in cancellous bone formation and mitigate disuse-induced loss of bone mass. The purpose of this study was to characterize the independent and combined effects of DOB and hindlimb unloading (HU) on cancellous bone microarchitecture, tissue-level bone cell activity, and osteocyte apoptosis. Male Sprague-Dawley rats, aged 6-mos, were assigned to either normal cage activity (CC) or HU (n= 18/group) for 28 days. Animals were administered either daily DOB (4 mg/kg BW/d) or an equal volume of saline (VEH) (n= 9/gp). Unloading resulted in significantly lower distal femur cancellous BV/TV (-33{\%}), Tb.Th ( -11{\%}), and Tb.N (-25{\%}) compared to ambulatory controls (CC-VEH). DOB treatment during HU attenuated these changes in cancellous bone microarchitecture, resulting in greater BV/TV (+29{\%}), Tb.Th (+7{\%}), and Tb.N (+21{\%}) vs. HU-VEH. Distal femur cancellous vBMD (+11{\%}) and total BMC (+8{\%}) were significantly greater in DOB- vs. VEH-treated unloaded rats. Administration of DOB during HU resulted in significantly greater osteoid surface (+158{\%}) and osteoblast surface (+110{\%}) vs. HU-VEH group. Furthermore, Oc.S/BS was significantly greater in HU-DOB (+55{\%}) vs. CC-DOB group. DOB treatment during unloading fully restored bone formation, resulting in significantly greater bone formation rate (+200{\%}) than in HU-VEH rats. HU resulted in an increased percentage of apoptotic cancellous osteocytes (+85{\%}), reduced osteocyte number (-16{\%}), lower percentage of occupied osteocytic lacunae (-30{\%}) as compared to CC-VEH, these parameters were all normalized with DOB treatment. Altogether, these data indicate that beta1AR agonist treatment during disuse mitigates negative changes in cancellous bone microarchitecture and inhibits increases in osteocyte apoptosis.",
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