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

Abstract

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 ...

The myokine irisin increases cortical bone mass

“…1D. Dynamic histomorphometry was performed as described (53). The threepoint bending test was carried out according to a previous protocol (54).…”

Pituitary-bone connection in skeletal regulation

“…Additionally, bone marrow stromal cells from FSHR -/-mice showed significantly greater colony-forming (Cfu-f) potential, suggesting a profound increase in osteoblastogenesis in the absence of the FSHR. Importantly, antibody injections did not affect serum estrogen levels in wild type mice [35]. Collectively, our studies provide clear evidence that lowering FSH in a hypogonadal state prevents bone loss.…”

“…We found that this antibody not only attenuated osteoclastogenesis induced by FSH in vitro, but also prevented the loss of bone post-ovariectomy [35,36]. Most importantly, we noted through a detailed histomorphometric analysis that while bone resorption was reduced, bone formation was surprisingly elevated significantly [35].…”

“…We have recently developed a polyclonal antibody against the 13-amino-acid-long conserved peptide sequence of the computationally defined FSHR-binding domain of FSHβ [35,36]. We found that this antibody not only attenuated osteoclastogenesis induced by FSH in vitro, but also prevented the loss of bone post-ovariectomy [35,36].…”

Epitope-specific monoclonal antibodies to FSHβ increase bone mass

“…By modeling the Fshr-Fsh interaction in mouse, we developed a polyclonal antibody to a 13-amino acid sequence in the binding domain of Fshβ (12,15,16).…”