We will study the interactions of two sex hormones, FSH and estrogen, in regulating bone turnover. Our work shows that both FSH and estrogen receptors modulate bone differentiation and activity. Our findings, and those of others, show that crosstalk between these regulatory systems is mediated by secondary signals including TNFa. We will test the hypothesis that estrogen is anabolic, and FSH catabolic, for bone mass. In the menopause, estrogen drops to low levels and FSH climbs to high levels, leading to rapid bone loss. However, the relationship of FSH and estrogen receptor expression during bone cell differentiation is poorly understood. We will study this using human cells as the primary model. Knockout mice will also be used as sources of cells, and for long-term studies in vivo.
Aim 1 will establish how FSH and estrogen responses are regulated during differentiation of human nontransformed osteoblast and osteoclast precursor cells. This will study the hypothesis that FSH-R, mainly in an alternatively spliced form, is expressed on osteoblast MSC precursors and on osteoclasts. In contrast, estrogen, mainly via ERa, is believed to affect osteoclasts only during differentiation, while ERa is strongly expressed late in osteoblast differentiation, where it regulates bone formation.
Aim 2 will determine mechanisms of interaction of sex steroids and FSH signaling in osteoblasts and in osteoclasts. This will include quantifying the relative effects of FSH and estrogen on human osteoclast differentiation and survival. Mechanisms of cell response to FSH will be characterized. The production of TNFa, in human bone cells in response to FSH will be defined. In addition, potential counter-regulation of estrogen and FSH signaling will be studied. Effects of FSH on differentiation and survival of human osteoblasts will be evaluated, including interaction with estrogen effects. Finally, we will use a knockout mouse model to uncouple FSH-R from estrogen effects, and determine the effects on bone formation. FSH-R-/- animals will be used for studies comparing bone turnover to ovariectomized animals, with and without estrogen replacement, as functions of animal age. These studies will clarify understanding of postmenopausal bone loss, improve the ability to monitor treatment, and may improve the long-term management of hypogonadal bone disease.
. Women at the menopause have rapid bone loss, but estrogen replacement only partially prevents this. We discovered that the pituitary hormone FSH, which regulates estrogen production, may cause bone loss directly. We will study this FSH response in bone to provide new insights into prevention of osteoporosis.
|Papachristou, Nicholaos I; Blair, Harry C; Kypreos, Kyriakos E et al. (2017) High-density lipoprotein (HDL) metabolism and bone mass. J Endocrinol 233:R95-R107|
|Blair, Harry C; Soboloff, Jonathan; Robinson, Lisa J et al. (2016) Suppression of arthritis-induced bone erosion by a CRAC channel antagonist. RMD Open 2:e000093|
|Blair, Harry C; Sepulveda, Jorge; Papachristou, Dionysios J (2016) Nature and nurture in atherosclerosis: The roles of acylcarnitine and cell membrane-fatty acid intermediates. Vascul Pharmacol 78:17-23|
|Tourkova, Irina L; Witt, Michelle R; Li, La et al. (2015) Follicle stimulating hormone receptor in mesenchymal stem cells integrates effects of glycoprotein reproductive hormones. Ann N Y Acad Sci 1335:100-9|
|Zacherl, Janelle R; Tourkova, Irina; St Croix, Claudette M et al. (2015) Elaidate, an 18-carbon trans-monoenoic fatty acid, but not physiological fatty acids increases intracellular Zn(2+) in human macrophages. J Cell Biochem 116:524-32|
|Zacherl, Janelle R; Mihalik, Stephanie J; Chace, Donald H et al. (2014) Elaidate, an 18-carbon trans-monoenoic fatty acid, inhibits ?-oxidation in human peripheral blood macrophages. J Cell Biochem 115:62-70|
|Chen, Qian; Liu, Kai; Robinson, Andria R et al. (2013) DNA damage drives accelerated bone aging via an NF-?B-dependent mechanism. J Bone Miner Res 28:1214-28|
|Wang, Bin; Yang, Yanmei; Liu, Li et al. (2013) NHERF1 regulation of PTH-dependent bimodal Pi transport in osteoblasts. Bone 52:268-77|
|Tantikanlayaporn, Duangrat; Robinson, Lisa J; Suksamrarn, Apichart et al. (2013) A diarylheptanoid phytoestrogen from Curcuma comosa, 1,7-diphenyl-4,6-heptadien-3-ol, accelerates human osteoblast proliferation and differentiation. Phytomedicine 20:676-82|
|Zhu, Ling-Ling; Blair, Harry; Cao, Jay et al. (2012) Blocking antibody to the ýý-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis. Proc Natl Acad Sci U S A 109:14574-9|
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