Physical exercise is able to improve skeletal health. However, the mechanisms are poorly known. Irisin, a novel exercise-induced myokine, secreted by skeletal muscle in response to exercise, have been shown to mediate beneficial effects of exercise in many disorders. In the current study, we demonstrated that irisin promotes osteoblast proliferation, and increases the expression of osteoblastic transcription regulators, such as Runt-related transcription factor-2, osterix/sp7; and osteoblast differentiation markers, including alkaline phosphatase, collagen type 1 alpha-1, osteocalcin, and osteopontin in vitro. Irisin also increase ALP activity and calcium deposition in cultured osteoblast. These osteogenic effects were mediated by activating the p38 mitogen-activated protein kinase (p-p38 MAPK) and extracellular signal-regulated kinase (ERK). Inhibition of p38 MAPK by SB023580 or pERK by U0126 abolished the proliferation and up-regulatory effects of irisin on Runx2 expression and ALP activity. Together our observation suggest that irisin directly targets osteoblast, promoting osteoblast proliferation and differentiation via activating P38/ERK MAP kinase signaling cascades in vitro. Whether irisin can be utilized as the therapeutic agents for osteopenia and osteoporosis is worth to be further pursued.
Irisin is a product of fibronectin type III domain-containing protein (Fndc5) and is involved in the regulation of adipokine secretion and the differentiation of osteoblasts and osteoclasts. In this study, we aimed to determine whether irisin lacking affects glucose/lipid and bone metabolism. We knocked out the Fndc5 gene to generate irisin-lacking mice. Remarkable, irisin lacking was related to poor ‘browning response’, with a bigger size of the intraperitoneal white adipose cell and decreased a number of brown adipose cells in brown adipose of interscapular tissue. The irisin lacking mice had hyperlipidemia and insulin resistance, reduced HDL-cholesterol level, increased LDL-cholesterol level, and decreased insulin sensitivity. The lacking of irisin was associated with reduced bone strength and bone mass in mice. The increased number of osteoclasts and higher expression of RANKL indicated increased bone resorption in irisin lacking mice. The level of IL-6 and TNF-α also increased in irisin lacking mice. The results showed that irisin lacking was related to decreased ‘browning response’, glucose/lipid metabolic derangement, and reduced bone mass with increased bone resorption. Further studies are needed to confirm these initial observations and explore the mechanisms underlying the effects of irisin on glucose/lipid and bone metabolism.
The receptor activator of NF-κB ligand-induced osteoclast differentiation has a critical role in the process of bone metabolism. Overactivation of osteoclastogenesis may result in a series of diseases. Irisin, a novel myokine, which was first reported in 2012, has been proposed to mediate the beneficial metabolic effects of exercise. Studies have demonstrated that irisin targets osteoblasts by promoting osteoblast proliferation and differentiation; however, the underlying mechanism regarding the effect of irisin on osteoclasts remains elusive. Using 2 types of osteoclast precursor cells, RAW264.7 cells and mouse bone marrow monocytes, we showed that irisin promoted osteoclast precursor cell proliferation but inhibited osteoclast differentiation. Irisin down-regulated the expression of osteoclast differentiation marker genes, including receptor activators of NF-κB, nuclear factor of activated T cells, cytoplasmic 1, cathepsin K, and tartrate-resistant acid phosphatase (TRAP), as well as decreasing the number of TRAP-positive multinucleated cells and hydroxyapatite resorption pits. Furthermore, we showed that irisin suppressed the NF-κB signaling pathway, but activated the p38 and JNK signaling pathways. In the presence of an inhibitor of p38 and JNK, irisin-induced promotion of RAW264.7 cell proliferation was attenuated. However, irisin-induced inhibition of osteoclast differentiation was not affected by either the p38 or JNK signaling pathway. Our study suggested the direct effect of irisin on osteoclastogenesis and revealed the mechanism responsible for the therapeutic potential of irisin in bone metabolism disease.-Ma, Y., Qiao, X., Zeng, R., Cheng, R., Zhang, J., Luo, Y., Nie, Y., Hu, Y., Yang, Z., Zhang, J., Liu, L., Xu, W., Xu, C. C., Xu, L. Irisin promotes proliferation but inhibits differentiation in osteoclast precursor cells.
Asthenozoospermia is a common cause of male infertility associated with the reduced motility and/or abnormal morphology of spermatozoa, although its etiology remains incompletely understood. Multiple morphological abnormalities of the sperm flagella (MMAF) is one of the main causes of asthenozoospermia. However, the MMAF-associated genes identified to date cannot explain all the human MMAF cases. Herein, a loss-of-function mutation of DNAH8 was identified in an asthenozoospermia patient with MMAF. Moreover, the negative effect of this mutation on DNAH8 expression was confirmed by immunofluorescence staining and western blotting. Remarkably, it is the first time that DNAH8 is suggested to be associated with human MMAF. Our findings provide strong evidence that a loss-offunction mutation in DNAH8 can cause male infertility with MMAF and that DNAH8 is essential for sperm flagellar formation.
Data from 19,950 women were retrospectively analysed to determine the effect of chromosomal polymorphisms on female infertility and pregnancy outcome; fertile women were used as controls. Frequency of chromosomal polymorphisms and adverse pregnancy outcomes were compared between groups. A significantly higher incidence of chromosomal polymorphisms was found in total infertile patients, and patients with tubal infertility, ovulatory dysfunction, cervical and uterine abnormalities, and unexplained infertility compared with controls (5.53% [P < 0.001], 4.86% [P = 0.012] 5.40% [P < 0.001], 5.75% [P < 0.001] and 8.51% [P < 0.001], versus 3.74%, respectively). Infertile women had a higher incidence of 9qh+ and inv(9) compared with controls (P < 0.001 and P = 0.027). Logistic regression analysis showed an effect of chromosomal polymorphisms on female infertility (adjusted OR 1.662, 95% CI 1.551 to 1.796, P < 0.001). All couples reported a phenotypically normal baby. In control and tubal infertility groups, miscarriage rates were higher in women with chromosomal polymorphisms than in women with normal chromosomes (4.95% versus 0.96%, P = 0.001 and 6.17% versus 1.08%, P < 0.001). Preterm birth rate showed a similar trend. Chromosomal polymorphisms adversely affected spontaneous miscarriage rates (adjusted OR 1.625, 95% CI 1.514 to 1.769, P = 0.005).
The essence of primary ovarian insufficiency (POI) is the premature exhaustion of primordial follicles in the follicle pool, which is caused by the excessive premature activation of primordial follicles after birth. Bisphenol A (BPA) exposure promotes the transition of primordial follicles to primary follicles, thus the number of primordial follicles in the primordial follicle pool decreases significantly. However, the molecular mechanisms underlying abnormal follicle activation are poorly understood. Phosphatase and tensin homologue (PTEN) signal system is a negative regulator of follicle activation, which is called the brake of follicle activation. Besides, BPA induces Michigan Cancer Foundation-7 breast cancer cells proliferation by dysregulating PTEN/serine/threonine kinase/p53 axis. Whether BPA initiates the excessive premature activation of primordial follicles in the mouse ovaries via PTEN signaling pathway is unclear. In this study, we treated 6-week-old female CD-1 mice with different concentrations of BPA to study the effect of BPA on follicular activation and development in vivo, as well as the role of PTEN signaling in this process. We observed that BPA in concentrations from 1 μg/kg to 10 mg/kg groups downregulated PTEN expression and initiated excessive premature activation of primordial follicles in the mouse ovaries, and this effect was partly reversible by PTEN overexpression. Our results improve the understanding of both the effect of BPA in occurrence of POI and molecular mechanisms underlying initiation of primordial follicle pool activation, thus providing insight for POI treatment and theoretical basis for reducing the risk of POI.
Objective: Osteoporosis has imposed a heavy socioeconomic burden worldwide, especially in postmenopausal women. As a newly found protein, irisin has an important physiological role in bone metabolism. This meta-analysis intends to identify the association between circulating irisin levels and osteoporosis. Methods: This meta-analysis was conducted following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guideline. A comprehensive search of five databases was performed from inception to January 2019. Studies with original date on middle-aged and older participants were included. Data were analyzed according to study characteristics and heterogeneity between studies. The quality of each study and the presence of publication bias were assessed by Newcastle-Ottawa score (NOS) and normal quantile plot. Results: Seven studies, with a total of 1,018 participants, conducted in four countries, were included. Six of them were identified as high-quality research. Five studies included postmenopausal women, and two studies included both men and women. Possible publication bias was found in the analysis of irisin and osteoporosis. Pooled analysis indicated decreased irisin levels in osteoporotic participants (mean difference −87.91, 95% CI, −92.56 to −83.25). Subgroup analysis revealed an even lower level of irisin in postmenopausal women and in participants with a history of fractures. Analysis on associations between irisin and femoral neck or lumbar spine bone mineral density showed a weak positive correlation. Conclusions: The findings of this analysis suggested that circulating irisin levels were decreased in middle-aged and older participants with osteoporosis. Irisin was positively correlated with bone mineral density.
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