A novel cell-autonomous role for β-adrenergic receptor signaling in osteoclasts

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The sympathetic nervous system (SNS) is an important regulator of bone, and may contribute to bone pathology during aging. SNS activity is also heightened in post-menopausal women, causing reduced bone formation by osteoblasts and increased bone resorption by osteoclasts, which leads to bone loss. Large meta- analyses, osteoporosis cohort studies (preliminary data from co-I Dr. Lary) and new prospective trials, consistently show that β-adrenergic receptor (βAR) antagonists (i.e. β-blockers) are associated with reduced fracture risk, increased bone mineral density (BMD), and reduced bone resorption. However, mechanistic studies have focused largely on the osteoblast as the target of SNS activity. Humans and mice have three βARs: β1AR, β2AR and β3AR. The gene encoding β2AR (Adrb2) is highly expressed in bone, which also expresses lower levels of Adrb1, but does not express Adrb3. In mice, Adrb2 deletion in osteoblasts improves bone formation and prevents receptor activator of nuclear factor-kappa B ligand (RANKL)-mediated osteoclast recruitment after stimulation with a β-agonist. In humans, β1-selective β-blockers are used most often, but their selectivity is not absolute, and many still bind β2AR. Propranolol, a non-selective β-blocker, increases BMD in the majority of preclinical studies. Results from our laboratory show that propranolol can limit bone resorption directly in vitro, and in vivo without changing RANKL levels. This is in contrast to the established dogma that osteoblast expression of β2AR regulates osteoclasts only indirectly via RANKL. Our proposed work will resolve the outstanding mechanistic questions of how β1AR and β2AR directly influence osteoclast differentiation and what their contributions are to age- and SNS-related bone loss. We propose a novel hypothesis that βAR signaling in osteoclasts promotes differentiation and resorption and contributes to bone loss in vivo. To fully characterize βAR receptor subtypes and novel signaling mechanisms in osteoclasts, and to determine the contribution of βAR subtypes to in vivo phenotypes of bone density and bone remodeling, we propose a combination of genetic and pharmacologic in vivo and in vitro approaches in the following Specific Aims. Specific Aim 1: We will identify signaling mechanisms activated by specific βARs in osteoclasts. We expect that we will identify novel and established target pathways to test in vivo for efficacy in modulating bone resorption. Specific Aim 2: We will test the relative contributions of osteoclast β1AR and β2AR to SNS- mediated and aging-related bone loss in vivo. The SNS has been implicated in osteoporosis, but the role of βARs in osteoclasts has never been investigated in this condition. We hypothesize that both deletion of β1AR and β2AR, specifically in the osteoclasts, will attenuate βAR agonist-induced and aging-related bone loss in mice. Our work will provide a more complete understanding of the role of SNS signaling in age-related bone loss in vivo, and will lead to studies targeting specific osteoclast βARs and downstream signaling pathways for treatment of bone diseases.