Inner Ear Vestibular Signals Regulate Bone Remodeling via the Sympathetic Nervous System

Abstract

The inner ear vestibular system has numerous projections on central brain centers that regulate sympathetic outflow, and skeletal sympathetic projections affect bone remodeling by inhibiting bone formation by osteoblasts and promoting bone resorption by osteoclasts. In this study, we show that bilateral vestibular lesions in mice cause a low bone mass phenotype associated with decreased bone formation and increased bone resorption. This reduction in bone mass is most pronounced in lower limbs, is not associated with reduced locomotor activity or chronic inflammation, and could be prevented by the administration of the β-blocker propranolol and by genetic deletion of the β2-adrenergic receptor, globally or specifically in osteoblasts. These results provide novel experimental evidence supporting a functional autonomic link between central proprioceptive vestibular structures and the skeleton. Because vestibular dysfunction often affects the elderly, these results also suggest that age-related bone loss might have a vestibular component and that patients with inner ear pathologies might be at risk for fracture. Lastly, these data might have relevance to the bone loss observed in microgravity, as vestibular function is altered in this condition as well. © 2015 American Society for Bone and Mineral Research.

Keywords: AGING; BONE; INNER EAR; MICROGRAVITY; OSTEOPOROSIS; SYMPATHETIC NERVOUS SYSTEM; VESTIBULAR SYSTEM; β2-ADRENERGIC RECEPTOR.

Fig. 1

VBX-induced bone loss in mice 1 month after VBX. (A) Vestibular syndrome score (in arbitrary unit), 3, 15, and 30 days after VBX. (B) Serum TNFα level 1 month after sham operation or VBX. (C) Trabecular bone volume ratio (BV/TV), trabeculae number (Tb.N), thickness (Tb.Th), and space (Tb.Sp), osteoblast and osteoclast surface per bone surface (Ob.S/BS, Oc.S/BS), osteoblasts and osteoclasts number per bone perimeter (N.Ob/B.Pm, N.Oc/B.Pm), mineralized surface per bone surface (MS/BS), bone formation rate per bone surface (BFR/BS), and mineral apposition rate (MAR) 1 month after sham operation or VBX. (D) Ambulatory distance 3 and 27 days after sham operation or VBX. (A–D) n = 8–10/group; error bars are standard deviations; ^*p < 0.05, ^**p < 0.01, ^***p < 0.005 versus WT PBS.

Fig. 2

VBX-induced bone loss in young adult mice is transient. (A) Trabecular bone volume ratio (BV/TV) 1, 3, and 6 months after VBX lesion (μCT measurements). (B) Ucp1 expression in brown adipose tissue 1, 3, and 6 months after VBX lesion. Values are normalized to WT PBS 1 month after lesion in B; n = 10/group; error bars are standard deviations; ^**p < 0.01, ^***p < 0.005; ^$$$p < 0.005 versus WT PBS 1 month after lesion.

Fig. 3

βAR blockade prevents VBX-induced bone loss. (A) Vestibular syndrome score (in arbitrary unit) 3, 15, and 30 days after VBX (***p < 0.005 versus sham). (B) Trabecular bone volume ratio (BV/TV) in 3-month-old β2AR^+/+ and β2AR^−/− mice subjected to sham or VBX (μCT measurements). (C) Trabecular bone volume ratio (BV/TV) in 3-month-old β2AR2.3col1^+/+ and β2AR2.3col1^−/− mice subjected to sham or VBX (μCT measurements). (D) Trabecular bone volume ratio (BV/TV) in mice subjected to sham or VBX, treated or not with propranolol (Pro., 0.5 g/L). (A–D) n = 10/group; error bars are standard deviations; ^*p < 0.05, ^**p < 0.01, ^***p < 0.005.