The adipocyte-derived hormone leptin acts on multiple organs, including bone. The specific effects of leptin on bone metabolism are controversial, with evidence for direct bone anabolic actions and indirect hypothalamic- mediated catabolic actions. The proposed research is designed to test the novel hypothesis that leptin plays a previously unrecognized but important role in the etiology of metabolic bone disease. Leptin acts as an on/off permissive factor signaling brain and bone cells that energy reserves are adequate to support bone growth and turnover. However, leptin also functions as a proinflammatory cytokine and can modulate both innate and adaptive immune responses. Based on extensive preliminary data, it is hypothesized that leptin, by exacerbating pathogenic proinflammatory immune responses, acts as an important comorbidity factor to amplify inflammation-driven bone loss. The proposed leptin-regulated pathways target osteoblasts, immune cells, and the hypothalamus. Specifically, hyperleptinemia contributes to elevated proinflammatory responses, resulting in additional collateral damage to bone by amplifying the detrimental skeletal effects caused by coexisting inflammation. The underlying inflammation can be due to a variety of factors, including infection, periodontal disease, asthma, estrogen deficiency, arthritis, or orthopedic implant debris. Preliminary studies showing that leptin-deficient ob/ob mice are highly resistant to bone loss induced by polyethylene particles (placed onto calvarium to model arthroplasty wear particle-induced osteolysis) strongly support this hypothesis. We propose to test our hypothesis by accomplishing two Aims.
Aim 1 : Define the contribution of hyperleptinemia to inflammation-driven bone loss. Local inflammation will be induced in WT and leptin-deficient ob/ob mice in which levels of leptin receptor occupancy will be experimentally manipulated. Magnitude of inflammation, local and systemic bone loss, and activation of immune cells in the spleen will be measured.
Aim 2 : Determine the respective roles of peripheral versus hypothalamic leptin signaling in inflammation-driven bone loss. Studies are designed to evaluate the extent to which leptin modulates immune function directly via activation of leptin receptors on immune cells and/or indirectly by increasing sympathetic signaling through a hypothalamic relay, and if these regulatory pathways converge to exacerbate inflammation-driven bone loss. To overcome the confounding effects of surgery-associated inflammation, long duration hypothalamic leptin gene therapy will be used to selectively restore leptin signaling in the hypothalamus of ob/ob mice. Peripheral leptin signaling will be selectively restored to immune cells in leptin receptor-deficient db/db mice by transplantation of WT hematopoietic stem cells. Successful completion of the proposed research will have a major impact on the emerging field of osteoimmunology, and is expected to radically alter our understanding of the physiological and pathological actions of leptin. Finally, determining the precise role of leptin-modulated peripheral and central pathways is expected identify targets to prevent/treat inflammation-driven bone loss.

Public Health Relevance

Leptin is a hormone that acts on multiple organs, including the immune system and bone. The proposed research has been designed to test the novel hypothesis that leptin, by acting as an immune system modulator, is a key contributing factor to bone loss caused by inflammation. This knowledge is important because chronic inflammation results in bone loss, a common cause of bone fractures in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR060913-02
Application #
8333422
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Sharrock, William J
Project Start
2011-09-16
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$328,950
Indirect Cost
$103,950
Name
Oregon State University
Department
Nutrition
Type
Other Domestic Higher Education
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97339
Turner, Russell T; Philbrick, Kenneth A; Wong, Carmen P et al. (2014) Morbid obesity attenuates the skeletal abnormalities associated with leptin deficiency in mice. J Endocrinol 223:M1-15
Iwaniec, Urszula T; Turner, Russell T (2013) Failure to generate bone marrow adipocytes does not protect mice from ovariectomy-induced osteopenia. Bone 53:145-53
Turner, Russell T; Iwaniec, Urszula T; Wong, Carmen P et al. (2013) Acute exposure to high dose ýý-radiation results in transient activation of bone lining cells. Bone 57:164-73
Turner, Russell T; Kalra, Satya P; Wong, Carmen P et al. (2013) Peripheral leptin regulates bone formation. J Bone Miner Res 28:22-34