Sex-specific effects of estrogen and androgen on gene expression in human monocyte-derived osteoclasts

Abstract

Estrogen and androgen are both critical for the maintenance of bone, but the target cells, mechanisms, and responses could be sex-specific. To compare sex-specific actions of estrogen and androgen on osteoclasts, human peripheral blood mononuclear precursor cells from adult Caucasian males (n = 3) and females (n = 3) were differentiated into osteoclasts and then treated for 24 h with 17β-estradiol (10 nM) or testosterone (10 nM). Gene expression was studied with a custom designed qPCR-based array containing 94 target genes related to bone and hormone action. In untreated osteoclasts, 4 genes showed significant gender differences. 17β-estradiol significantly affected 12 genes in osteoclasts from females and 6 genes in osteoclasts from males. Fifteen of the 18 17β-estradiol-responsive genes were different in the cells from the two sexes; 2 genes affected by 17β-estradiol in both sexes were regulated oppositely in the two sexes. Testosterone significantly affected 6 genes in osteoclasts from females and 2 genes in osteoclasts from males; all except one were different in the two sexes. 17β-estradiol and testosterone largely affected different genes, suggesting that conversion of testosterone to 17β-estradiol had a limited role in the responses. The findings indicate that although osteoclasts from both sexes respond to 17β-estradiol and testosterone, the effects of both 17β-estradiol and testosterone differ in the two sexes, highlighting the importance of considering gender in the design of therapy.

The effects of orchidectomy and supraphysiological testosterone administration on trabecular bone structure and gene expression in rats

“…The trabecular structure of the ORX group was more porous compared to the SH and TE group. while estradiol treatment affected six osteoclastic genes in monocyte-derived osteoclasts donated by men [23]. Hence, we suggest that osteoporosis due to testosterone deficiency in young rats was due to an imbalance in bone remodeling process, whereby reduced bone formation in combination with preserved bone resorption lead to a net bone loss, indicated by degenerative structural change in the trabecular bone.…”

Association of serum inorganic phosphate with sex steroid hormones and vitamin D in a nationally representative sample of men

“…There are several ways in which sex steroid hormones may influence the dynamic of bone turnover. Directly, both estrogen and testosterone were suggested to modulate gene expression leading to shortened osteoclasts lifespan while prolonging that of osteoblasts in a gender- and site-specific fashion (Kawano et al , 2003; Michael et al , 2005; Nakamura et al , 2007; Imai et al , 2009; Wang & Stern, 2011; Yang et al , 2013). Through bone regulators, sex steroid hormones may also indirectly interfere with bone metabolism, as shown by inhibition of PTH-stimulated formation of osteoclasts following in vitro estradiol treatment (Liu et al , 2002).…”

“…Sex steroid hormones may affect Pi levels through modulation of Pi regulators as levels of PTH and vitamin D are influenced by estrogen (Liu et al , 2002; Uebelhart et al , 2009; Wang & Stern, 2011). Also, sex steroid hormones indirectly favor osteoblasts (Yang et al , 2013), which produce FGF-23, and treatment with estrogen results in higher FGF-23 mRNA and serum levels in vitro and in vivo (Carrillo-Lopez et al , 2009).…”

Sex and the single nucleotide polymorphism: Exploring the genetic causes of skeletal sex differences

“…For example, osteoclasts from human monocytes were found not only to differ in their gene expression by sex but also to display sex-specific responses to 17-β estradiol and testosterone treatments. (19) And in fact, although only four genes were differentially expressed by sex, the addition of hormone treatments resulted in more genes with larger expression differences than were apparent by sex alone. (19) For instance, LRP5 (an important component of the Wnt-signaling pathway in bone) showed no expression differences by sex, but estrogen treatment resulted in a 265.3-fold increase in expression in female osteoclasts and only a 7.4-fold increase in expression in male osteoclasts.…”

“…(19) And in fact, although only four genes were differentially expressed by sex, the addition of hormone treatments resulted in more genes with larger expression differences than were apparent by sex alone. (19) For instance, LRP5 (an important component of the Wnt-signaling pathway in bone) showed no expression differences by sex, but estrogen treatment resulted in a 265.3-fold increase in expression in female osteoclasts and only a 7.4-fold increase in expression in male osteoclasts. Similarly, testosterone treatment had a large effect in female osteoclasts and none in males.…”