We reported recently that the posterior pituitary hormone oxytocin (OT) thought primarily to regulate lactation and social bonding is anabolic to the skeleton. Heterozygote mice with circulating OT reduced to half that of wild type mice showed no lactation defect, but instead displayed severe osteopenia and reduced bone formation. Bone resorption remained unaffected, likely due to the opposing actions of OT on osteoclast formation and function. Together the data suggest that the bone forming action of OT is dominant, and perhaps more ancient than its effect on the breast. Expectedly, OT injected into wild type mice increased bone mass by enhancing osteoblastogenesis, whereas in stromal cell cultures, it stimulated mineralized colony formation. Furthermore, we found recently that bone marrow osteoblasts not only possess abundant OT receptors (Oxtrs), but also produce OT. This means that an autocrine OT circuit in marrow could potentially amplify the bone forming action of injected OT. We hypothesize that OT is an anabolic bone hormone, and that its action is mediated through an osteoblast Oxtr, which when stimulated by OT, produces OT locally in an autocrine loop.
In Specific Aim 1, we will investigate whether injected OT can restore the lost bone in aging and hypogonadal mice.
In Specific Aim 2, we will elucidate, through cell-selective genetic ablation of the Oxtr, whether osteoblasts, osteoclasts or both cells participate in the action of OT.
In Specific Aim 3, we will determine whether marrow OT is required for the bone forming action of injected OT using OT-/- mice and bone marrow transplantation. Our studies should help establish OT and Oxtrs as potential targets for treating human osteoporosis.

Public Health Relevance

Osteoporosis affects at least 50 million Americans who suffer from around 2.4 million debilitating fractures each year resulting in an overall expense of ~$18 billion. The present proposal underpins our more recent finding that a pituitary hormone, oxytocin (OT), regulates skeletal integrity. We will utilize a complement of pharmacological and mouse genetic studies to determine whether OT or its receptor can be leveraged to treat osteoporosis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG040132-03
Application #
8489237
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M1))
Program Officer
Williams, John
Project Start
2011-08-15
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$361,849
Indirect Cost
$148,369
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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