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.
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.
|Yau, Mabel; Haider, Shozeb; Khattab, Ahmed et al. (2017) Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11?-hydroxysteroid dehydrogenase type 2 deficiency. Proc Natl Acad Sci U S A 114:E11248-E11256|
|Liu, Tong; Zhang, Hao; Sun, Li et al. (2017) FSIP1 binds HER2 directly to regulate breast cancer growth and invasiveness. Proc Natl Acad Sci U S A 114:7683-7688|
|Liu, Peng; Ji, Yaoting; Yuen, Tony et al. (2017) Blocking FSH induces thermogenic adipose tissue and reduces body fat. Nature 546:107-112|
|Khattab, Ahmed; Haider, Shozeb; Kumar, Ameet et al. (2017) Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11?-hydroxylase deficiency. Proc Natl Acad Sci U S A 114:E1933-E1940|
|Kushwaha, Priyanka; Khedgikar, Vikram; Sharma, Deepika et al. (2016) MicroRNA 874-3p Exerts Skeletal Anabolic Effects Epigenetically during Weaning by Suppressing Hdac1 Expression. J Biol Chem 291:3959-66|
|Khattab, Ahmed; Yuen, Tony; Al-Malki, Sultan et al. (2016) A rare CYP21A2 mutation in a congenital adrenal hyperplasia kindred displaying genotype-phenotype nonconcordance. Ann N Y Acad Sci 1364:5-10|
|Sun, Li; Tamma, Roberto; Yuen, Tony et al. (2016) Functions of vasopressin and oxytocin in bone mass regulation. Proc Natl Acad Sci U S A 113:164-9|
|Liu, Peng; Ping, Yilin; Ma, Meng et al. (2016) Anabolic actions of Notch on mature bone. Proc Natl Acad Sci U S A 113:E2152-61|
|Iqbal, Jameel; Yuen, Tony; Sun, Li et al. (2016) From the gut to the strut: where inflammation reigns, bone abstains. J Clin Invest 126:2045-8|
|Pazianas, Michael; Kim, Se-min; Yuen, Tony et al. (2015) Questioning the association between bisphosphonates and atypical femoral fractures. Ann N Y Acad Sci 1335:1-9|
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