Age-related bone loss is characterized by uncoupled skeletal remodeling with loss of trabecular and cortical bone. In addition, aging also profoundly affects adipose tissue through atrophy of preformed brown adipose tissue (BAT), lipid deposition in non-adipose sites, and changes in white adipose tissue (WAT) distribution. The central nervous system (CNS) modulates adipose tissue function and bone turnover through efferent pathways from the SNS. In bone, catecholamines bind to ?2 adrenergic receptors (AR) on osteoblasts to suppress bone formation and increase resorption while in BAT, catecholamines act on ?3 adrenergic receptors to increase non-shivering thermogenesis. We recently characterized a spontaneous mutant mouse on a B6 background, Misty, that has non-functioning BAT, low body temperature, enhanced SNS tone, low trabecular bone mass with a small periosteal envelope. Misty has a 'loss of function'mutation in Dock7, a protein highly expressed in Schwann cells that affects cell migration. Dock7 is phosphorylated by ErbB2 a tyrosine kinase receptor that heterodimerizes with other ErbB receptors to enhance cell proliferation through the MAPK and PI3K pathways. In addition Dock7 activates a family of RhoGTPases that regulate bone cell growth and intracellular lipolysis. We noted that the Dock 7 mutation in Misty was associated with age-accelerated bone loss as well as increased energy expenditure, higher catecholamines, reduced bone formation and increased bone resorption. In WAT depots, Misty had brown-like adipocytes suggesting that the SNS is compensating for loss of BAT but that the SNS drive may also be causing age-related skeletal loss. In support of that tenet, short-term treatment of Misty with propranolol for four weeks partially rescued the aBMD deficit and increased bone mass by 7%. Taking these lines of evidence together, we hypothesize that the primary abnormality in Misty is premature senescence of BAT causing increased SNS activity at the expense of bone mass. But because Dock7 is in the ErbB signaling pathway and activates RhoGTPase, we postulate there is also a cell-autonomous defect in Misty that causes primary BAT dysfunction and impaired osteoblast activity.
Two specific aims are proposed: 1-To fully characterize the skeletal and metabolic phenotype of Misty and littermate controls to 78 months of age, and test the hypothesis that SNS overactivity drives skeletal loss in three ways: a- treatment with propranolol;b- crossing Misty with an osteoblast-specific ?2 receptor -/- mouse;c-high fat feeding. 2-To determine cell autonomous effects of the Dock7 mutation on brown adipocytes and osteoblasts by temporal expression profiling, signaling, and cell migration studies through the Rho GTPase and ErbB/MAPK/PI3K pathways in Misty and +/+ controls. In sum, we will determine the role of the CNS in regulating bone remodeling and determine how age-related changes in BAT may impact bone mass. Importantly, these studies will shed new light on the ErbB and Dock7 signaling pathways in bone and in BAT. Defining shared metabolic-skeletal networks may lead to new treatments for age-related osteoporosis.

Public Health Relevance

There are important public health implications in regards to this proposal. Most importantly, understanding the role of the sympathetic nervous system in regulating bone remodeling is paramount for determining individuals at risk and for designing therapies. In addition, exploring the role of brown adipose tissue in age-related osteoporosis provides fresh insight into a perplexing clinical problem, and opens new doorways for novel therapies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZAG1-ZIJ-5 (M1))
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Williams, John
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Maine Medical Center
United States
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Devlin, M J; Van Vliet, M; Motyl, K et al. (2014) Early-onset type 2 diabetes impairs skeletal acquisition in the male TALLYHO/JngJ mouse. Endocrinology 155:3806-16
Motyl, Katherine J; Bishop, Kathleen A; DeMambro, Victoria E et al. (2013) Altered thermogenesis and impaired bone remodeling in Misty mice. J Bone Miner Res 28:1885-97
Motyl, Katherine J; Rosen, Clifford J (2012) Understanding leptin-dependent regulation of skeletal homeostasis. Biochimie 94:2089-96