No abstract

The primitive neurohypophyseal nonapeptide oxytocin (OXT) has established functions in parturition, lactation, appetite, and social behavior. We have shown that OXT has direct actions on the mammalian skeleton, stimulating bone formation by osteoblasts and modulating the genesis and function of bone-resorbing osteoclasts. We deleted OXT receptors (OXTRs) selectively in osteoblasts and osteoclasts usingCol2.3CreandAcp5Cremice, respectively. Both male and femaleCol2.3Cre+:Oxtrfl/flmice recapitulate the low-bone mass phenotype ofOxtr+/−mice, suggesting that OXT has a prominent osteoblastic action in vivo. Furthermore, abolishment of the anabolic effect of estrogen inCol2.3Cre+:Oxtrfl/flmice suggests that osteoblastic OXTRs are necessary for estrogen action. In addition, the high bone mass inAcp5Cre+:Oxtrfl/flmice indicates a prominent action of OXT in stimulating osteoclastogenesis. In contrast, we found that in pregnant and lactatingCol2.3Cre+:Oxtrfl/flmice, elevated OXT inhibits bone resorption and rescues the bone loss otherwise noted during pregnancy and lactation. However, OXT does not contribute to ovariectomy-induced bone loss. Finally, we show that OXT acts directly on OXTRs on adipocytes to suppress the white-to-beige transition gene program. Despite this direct antibeiging action, injected OXT reduces total body fat, likely through an action on OXT-ergic neurons. Consistent with an antiobesity action of OXT,Oxt−/−andOxtr−/−mice display increased total body fat. Overall, the actions of OXT on bone mass and body composition provide the framework for future therapies for osteoporosis and obesity.

Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH agent a potential therapeutic for three global epidemics: obesity, osteoporosis, and hypercholesterolemia. Here, we report the generation, structure, and function of a first-in-class, fully humanized, epitope-specific FSH blocking antibody with a KD of 7 nM. Protein thermal shift, molecular dynamics, and fine mapping of the FSH–FSH receptor interface confirm stable binding of the Fab domain to two of five receptor-interacting residues of the FSHβ subunit, which is sufficient to block its interaction with the FSH receptor. In doing so, the humanized antibody profoundly inhibited FSH action in cell-based assays, a prelude to further preclinical and clinical testing.

We report that two widely-used drugs for erectile dysfunction, tadalafil and vardenafil, trigger bone gain in mice through a combination of anabolic and antiresorptive actions on the skeleton. Both drugs were found to enhance osteoblastic bone formation in vivo using a unique gene footprint and to inhibit osteoclast formation. The target enzyme, phosphodiesterase 5A (PDE5A), was found to be expressed in mouse and human bone as well as in specific brain regions, namely the locus coeruleus, raphe pallidus, and paraventricular nucleus of the hypothalamus. Localization of PDE5A in sympathetic neurons was confirmed by coimmunolabeling with dopamine β-hydroxylase, as well as by retrograde bone-brain tracing using a sympathetic nerve-specific pseudorabies virus, PRV152. Both drugs elicited an antianabolic sympathetic imprint in osteoblasts, but with net bone gain. Unlike in humans, in whom vardenafil is more potent than tadalafil, the relative potencies were reversed with respect to their osteoprotective actions in mice. Structural modeling revealed a higher binding energy of tadalafil to mouse PDE5A compared with vardenafil, due to steric clashes of vardenafil with a single methionine residue at position 806 in mouse PDE5A. Collectively, our findings suggest that a balance between peripheral and central actions of PDE5A inhibitors on bone formation together with their antiresorptive actions specify the osteoprotective action of PDE5A blockade.

Leydig cell tumors (LCTs) refer to tumors of the stroma of the genital strand, which are found mainly in postmenopausal women. The diagnosis of LCTs in postmenopausal women is associated with specific difficulties and is based on the identification of hyperandrogenism with clinical manifestations of virilization, which has an erased picture in postmenopausal women. LCTs require differential diagnosis with other causes of hyperandrogenism. We present the clinical case of a 55-year-old Russian postmenopausal patient with LCTs of the right ovary, significantly increased levels of androgens, and rapidly progressive clinical signs of hyperandrogenism. The patient underwent laparoscopic bilateral salpingo-oophorectomy, and the androgen indices reached average values by the first and third month after surgery. This case demonstrates that LCTs are often benign with a good prognosis and normalization of the clinical and laboratory manifestations of hyperandrogenism after surgical treatment. The type of surgery performed (bilateral salpingo-oophorectomy rather than unilateral) is recommended as the treatment of choice for LCTs in postmenopausal patients.