FSHR gene polymorphisms influence bone mineral density and bone turnover in postmenopausal women

Rendina, Domenico; Gianfrancesco, Fernando; Filippo, Gianpaolo De; Merlotti, Daniela; Esposito, Teresa; Mingione, Alessandra; Nuti, Ranuccio; Strazzullo, Pasquale; Mossetti, Giuseppe; Gennari, Luigi

doi:10.1530/eje-10-0043

Cited by 84 publications

(62 citation statements)

References 39 publications

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“…Patients with functional hypothalamic amenorrhea, in whom both FSH and estrogen are low, show slight to moderate skeletal defects (20). In contrast, women harboring an activating FSHR polymorphism, rs6166, have lower bone mass and higher bone resorption rates (8). Consistent with these human studies, the injection of FSH into rats has been shown to augment ovariectomy-induced alveolar bone loss (21).…”

Section: Discussionmentioning

confidence: 87%

“…Furthermore, amenorrheic women with high FSH levels >35 IU/L display greater decrements in bone density than those with a mean FSH of ∼8 IU/L (7). Likewise, women having activating FSH receptor (FSHR) polymorphisms have a low bone mass and high bone turnover (8). Together, these findings suggest that a rising FSH level may, in part, contribute to the perimenopausal bone loss that has traditionally been attributed solely to reduced estrogen levels.…”

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confidence: 99%

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Blocking antibody to the β-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis

Zhu

Blair

Cao

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

139

143

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Low estrogen levels undoubtedly underlie menopausal bone thinning. However, rapid and profuse bone loss begins 3 y before the last menstrual period, when serum estrogen is relatively normal. We have shown that the pituitary hormone FSH, the levels of which are high during late perimenopause, directly stimulates bone resorption by osteoclasts. Here, we generated and characterized a polyclonal antibody to a 13-amino-acid-long peptide sequence within the receptor-binding domain of the FSH β-subunit. We show that the FSH antibody binds FSH specifically and blocks its action on osteoclast formation in vitro. When injected into ovariectomized mice, the FSH antibody attenuates bone loss significantly not only by inhibiting bone resorption, but also by stimulating bone formation, a yet uncharacterized action of FSH that we report herein. Mesenchymal cells isolated from mice treated with the FSH antibody show greater osteoblast precursor colony counts, similarly to mesenchymal cells isolated from FSH receptor (FSHR) −/− mice. This suggests that FSH negatively regulates osteoblast number. We confirm that this action is mediated by signaling-efficient FSHRs present on mesenchymal stem cells. Overall, the data prompt the future development of an FSH-blocking agent as a means of uncoupling bone formation and bone resorption to a therapeutic advantage in humans.osteoporosis | sex steroids | skeletal anabolic | gonadotropin W omen lose over 3% of bone mass during late perimenopause at which time estrogen levels remain relatively unperturbed (1, 2). This bone loss begins 3 y before the last menstrual period (3), and arises from a profound elevation in bone resorption, which is not compensated by parallel increases in bone formation (4). Inhibiting bone resorption during this period with an anticatabolic agent, such as a bisphosphonate, selective estrogen receptor modulator, or estrogen itself, attenuates bone loss (5). However, estrogen use can be associated with increased breast cancer risk and designer estrogens have undesirable side effects. Further, growing concerns regarding oversuppression of bone turnover by bisphosphonates limit their use as early as perimenopause (5). The relatively small armamentarium for osteoporosis therapies, particularly for early and rapidly progressing bone loss, makes the advent of newer preventative strategies very desirable.A close examination of hormonal changes in women during late perimenopause shows that, whereas estrogen levels remain unperturbed, FSH levels have begun to rise, likely to compensate for failing ovaries (3). Strong correlations between rising serum FSH levels and bone loss have been documented, particularly in the Study of Women's Health Across Nations (SWAN) (2, 6). Furthermore, amenorrheic women with high FSH levels >35 IU/L display greater decrements in bone density than those with a mean FSH of ∼8 IU/L (7). Likewise, women having activating FSH receptor (FSHR) polymorphisms have a low bone mass and high bone turnover (8). Together, these findings suggest that a rising ...

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Section: Discussionmentioning

confidence: 87%

mentioning

confidence: 99%

Blocking antibody to the β-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis

Zhu

Blair

Cao

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

139

143

View full text Add to dashboard Cite

show abstract

“…Likewise, in a recent study, patients with functional hypothalamic amenorrhea, in whom both FSH and estrogen were low, showed slight to moderate skeletal defects [12]. Furthermore, women harboring an activating FSH receptor (FSHR) polymorphism, rs6166, have lower bone mass and higher resorption markers [13]; this attests to a role for FSHRs in human physiology, and perhaps, even human pathophysiology. Consistent with these human studies, exogenously administration of FSH to rats augmented ovariectomy-induced bone loss [14,15].…”

Section: Introductionmentioning

confidence: 93%

Further evidence that FSH causes bone loss independently of low estrogen

et al. 2012

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“…The results were impressive: the authors found that the single nucleotide polymorphism (SNP) rs6166 of the FSHR gene significantly influenced bone mass in postmenopausal women (29). Prior studies on AA rs6166 have associated this polymorphism with increased stimulation of the ovarian FSHR.…”

mentioning

confidence: 99%

“…Osteoporosis is a multifactorial disorder with genetic variation accounting for up to 80% variation in bone mineral density (28). Rendina et al sought to tie the role of FSH in causing osteoporosis to the genetic variability that exists among the human population (29). To do so, they examined 289 postmenopausal women for FSHR polymorphisms at two sites, rs1394205 and rs6166, and then analyzed the influence these polymorphisms had on bone mass and bone turnover (29).…”

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confidence: 99%

Commentary-FSH and bone 2010: evolving evidence

Iqbal

Sun²,

Zaidi

2010

European Journal of Endocrinology

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Bone loss due to menopause, natural or artificial, has been attributed solely to low estrogen. However, in a woman's life, the most precipitous bone loss begins 2 years prior to the last menstrual period, during which time estrogen levels are unperturbed whereas FSH is elevated. Our cell-based and mouse genetic studies have shown that FSH stimulates bone resorption by osteoclasts directly in a pituitarybone axis, independently of the estrogen effect. On the basis of this and evolving clinical and scientific evidence, we propose that elevated FSH contributes to bone loss across the menopausal transition, particularly during late perimenopause. In the current issue of the European Journal of Endocrinology, Rendina et al. strengthen the view for a primary role of FSH signaling in the regulation of bone mass and bone remodeling in humans by demonstrating that an 'activating' polymorphism AA rs6166 causes low bone mass and high bone turnover.

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FSHR gene polymorphisms influence bone mineral density and bone turnover in postmenopausal women

Cited by 84 publications

References 39 publications

Blocking antibody to the β-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis

Blocking antibody to the β-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis

Further evidence that FSH causes bone loss independently of low estrogen

Commentary-FSH and bone 2010: evolving evidence

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