The alteration of age‐related molecules in the bone marrow microenvironment is one of the driving forces in osteoporosis. These molecules inhibit bone formation and promote bone resorption by regulating osteoblastic and osteoclastic activity, contributing to age‐related bone loss. Here, we observed that the level of microRNA‐31a‐5p (miR‐31a‐5p) was significantly increased in bone marrow stromal cells (BMSCs) from aged rats, and these BMSCs demonstrated increased adipogenesis and aging phenotypes as well as decreased osteogenesis and stemness. We used the gain‐of‐function and knockdown approach to delineate the roles of miR‐31a‐5p in osteogenic differentiation by assessing the decrease of special AT‐rich sequence‐binding protein 2 (SATB2) levels and the aging of BMSCs by regulating the decline of E2F2 and recruiting senescence‐associated heterochromatin foci (SAHF). Notably, expression of miR‐31a‐5p, which promotes osteoclastogenesis and bone resorption, was markedly higher in BMSCs‐derived exosomes from aged rats compared to those from young rats, and suppression of exosomal miR‐31a‐5p inhibited the differentiation and function of osteoclasts, as shown by elevated RhoA activity. Moreover, using antagomiR‐31a‐5p, we observed that, in the bone marrow microenvironment, inhibition of miR‐31a‐5p prevented bone loss and decreased the osteoclastic activity of aged rats. Collectively, our results reveal that miR‐31a‐5p acts as a key modulator in the age‐related bone marrow microenvironment by influencing osteoblastic and osteoclastic differentiation and that it may be a potential therapeutic target for age‐related osteoporosis.
Juvenile white sturgeon were fed isonitrogenous diets containing 27.2% glucose, fructose, maltose, sucrose, lactose, dextrin, raw corn starch or cellulose for 8 wk. Growth, body composition, plasma chemistry (with the exception of glucose), and liver glucose-6-phosphate dehydrogenase (G6PDH, EC 184.108.40.206), malic enzyme (EC 220.127.116.11) and isocitrate dehydrogenase (ICDH, 18.104.22.168) activities of sturgeon were significantly (P less than 0.05) affected by the different dietary carbohydrate sources. Sturgeon fed either the maltose or glucose diets had the highest percent energy retained, followed by those fed either the dextrin, raw corn starch or sucrose diets, whereas those fed either the lactose, fructose or cellulose diets had the lowest. Sturgeon fed either the maltose or glucose diets were hyperlipidemic, having twice the amount of plasma total lipid, triacylglycerol and total cholesterol as fish fed the other carbohydrate sources. These two carbohydrate sources were also more lipogenic: maltose- or glucose-fed sturgeon had significantly higher body lipid and liver G6PDH, malic enzyme, and ICDH activities. The poor ability of sturgeon to utilize either sucrose or lactose appears to be due to low intestinal sucrase (EC 22.214.171.124) and lactase (EC 126.96.36.199) activities. Intestinal aminopeptidase (EC 188.8.131.52), maltase (EC 184.108.40.206), sucrase and lactase activities of sturgeon were not affected by feeding different carbohydrate sources for 8 wk.
To evaluate the potential use of a combination of antiresorption and bone formation-promoting agents as a treatment for postmenopausal osteoporosis, we examined the effects of combined and separate administration of estrogen ( 17,8-estradiol, 30 ;Lg/ kg per d, s.c.) and parathyroid hormone (rPTH 40 ;&g/ kg per d, s.c.) on the proximal tibia of ovariectomized (Ovx) rats. The treatments lasted for 4 wk and were initiated 1, 3, and 5 wk after surgery. Ovx resulted in rapid loss of cancellous bone volume (Cn-BV/TV) as well as trabecular connectivity, as determined by two dimensional strut analysis. When administered in a preventive mode, treatment beginning I wk postOvx, estrogen or PTH treatment alone preserved Cn-BV/TV and trabecular connectivity, and combined estrogen and PTH treatment caused a 40% increment in Cn-BV/TV while maintaining comparable trabecular connectivity with that seen in the Sham-operated animals. When administered in a curative mode to rats with established osteoporosis, treatments beginning 3 or 5 wk post-Ovx, estrogen or PTH treatment alone prevented further loss of connectivity and Cn-BV/TV, whereas the combined treatment resulted in as much as a 300% improvement in one of the parameters of trabecular connectivity, node to node strut length, and a 106% increase in Cn-BV/TV, with respect to the bone status at the initiation of treatment. The beneficial effects of this combined treatment derive from estrogen's ability to prevent accelerated bone resorption and, simultaneously, PTH's promotion of bone formation. These data demonstrate, in an animal model, that therapies can be devised to cure the skeletal defects associated with established osteoporosis. (J.
Juvenile white sturgeon (Acipenser transmontanus) were fed eight isonitrogenous and isoenergetic purified diets for 9 wk to study their ability to utilize different dietary lipids. Each diet contained 15% of control oil mixture (corn oil-cold liver oil-lard, 1:1:1), corn oil, cod liver oil, lard, linseed oil, soybean oil, safflower oil or canola oil. No significant (P > 0.05) differences in percentage of body weight increase, feed efficiency or body composition were observed among sturgeon fed the different lipids. Tissue fatty acid compositions most sensitive to dietary lipids were those of muscle and liver, whereas brain fatty acid composition was the least sensitive. Results of this study indicate that it is possible to increase the levels of (n-3) polyunsaturated and highly unsaturated fatty acids in sturgeon muscle by feeding the fish lipids high in these fatty acids for 9 wk.
Bisphosphonate‐related osteonecrosis of the jaw (BRONJ) is a detrimental side effect of the long‐term administration of bisphosphonates. Although macrophages were reported to be an important mediator of BRONJ, the detailed potential mechanism of BRONJ remains unclear. Here, we reported an elevated TLR‐4 expression in macrophages under action of zoledronic acid (ZA), resulting in enhanced M1 macrophage polarization and decreased M2 macrophage polarization both in vitro and in vivo. After inhibiting the TLR‐4 signaling pathway, the activation of the TLR‐4/NF‐κB signaling pathway and the induction of NF‐κB nuclear translocation and production of proinflammatory cytokines by ZA were suppressed in macrophages, thereby inhibiting M1 macrophage polarization. By utilizing the TLR‐4−/− mice, development of BRONJ was markedly ameliorated, and M1 macrophages were significantly attenuated in the extraction socket tissues in the TLR‐4−/− mice. Importantly, the systemic administration of the TLR‐4 inhibitor TAK‐242 improved the wound healing of the extraction socket and decreased the incidence rate of BRONJ. Taken together, our findings suggest that TLR‐4‐mediated macrophage polarization participates in the pathogenesis of BRONJ in mice, and TLR‐4 may be a potential target for the prevention and therapeutic treatment of BRONJ.—Zhu, W., Xu, R., Du, J., Fu, Y., Li, S., Zhang, P., Liu, L., Jiang, H. Zoledronic acid promotes TLR‐4‐mediated M1 macrophage polarization in bisphosphonate‐related osteonecrosis of the jaw. FASEB J. 33, 5208–5219 (2019). http://www.fasebj.org
Intermittent administration of PTH has been found to be an effective anabolic agent in cancellous bone. We have reported previously that combined treatment with PTH and estrogen in estrogen-deficient rats was beneficial in correcting established osteopenia. To determine if the beneficial effects of PTH therapy can be preserved by estrogen alone and whether PTH therapy can be effective in treating osteopenic subjects stabilized with estrogen, we have undertaken a "crossover" study in the rat model of estrogendeficiency induced osteopenia. Six-month-old female rats were ovariectomized and after 5 wk treated for 8 wk with vehicle, 30 rig/kg per day of rPTH(1-34) plus 15 ,.g/kg per day of 17fi-estradiol or 17f3-estradiol alone. One group from each treatment regimen was then sacrificed and for an additional 8 weeks the remaining rats were (a) maintained on their previous treatment; (b) "crossed over" to their reciprocal treatment; or (c) administered vehicle only. At the end of this second 8-wk treatment period all rats were sacrificed. Bone mineral density of the distal femur, histomorphometric measurements of the proximal tibia and mechanical testing of the distal femur and selected vertebral bodies were performed. Our results demonstrated that (a) the gains in bone mass, trabecular connectivity and mechanical strength induced by PTH can be maintained by estrogen alone, but are reversed when both agents are withdrawn; and (b) rats with established osteopenia, maintained on estrogen treatment alone, can derive the full beneficial effects from the addition of PTH to the treatment at a later date. These data indicate that combined and/or sequential use of antiresorptive and anabolic agents may be a promising approach to the treatment of osteoporosis. (J. Clin. Invest. 1995. 96:2331-2338
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