Conjugated linoleic acid and glucosamine supplements may prevent bone loss in aging by regulating the RANKL/RANK/OPG pathway.

The skeleton is a living organ that undergoes constant changes, including bone formation and resorption. It is affected by various diseases, such as osteoporosis, osteopenia, and osteomalacia. Nowadays, several methods are applied to protect bone health, including the use of hormonal and non-hormonal medications and supplements. However, certain drugs like glucocorticoids, thiazolidinediones, heparin, anticonvulsants, chemotherapy, and proton pump inhibitors can endanger bone health and cause bone loss. New studies are exploring the use of supplements, such as conjugated linoleic acid (CLA) and glucosamine, with fewer side effects during treatment. Various mechanisms have been proposed for the effects of CLA and glucosamine on bone structure, both direct and indirect. One mechanism that deserves special attention is the regulatory effect of RANKL/RANK/OPG on bone turnover. The RANKL/RANK/OPG pathway is considered a motive for osteoclast maturation and bone resorption. The cytokine system, consisting of the receptor activator of the nuclear factor (NF)-kB ligand (RANKL), its receptor RANK, and its decoy receptor, osteoprotegerin (OPG), plays a vital role in bone turnover. Over the past few years, researchers have observed the impact of CLA and glucosamine on the RANKL/RANK/OPG mechanism of bone turnover. However, no comprehensive study has been published on these supplements and their mechanism. To address this gap in knowledge, we have critically reviewed their potential effects. This review aims to assist in developing efficient treatment strategies and focusing future studies on these supplements.

Integration of pharmacodynamics and metabolomics reveals the therapeutic effects of 6-acetylacteoside on ovariectomy-induced osteoporosis mice.

BACKGROUND: 6-acetylacteoside (6-AA) is a phenylethanoid glycoside isolated from Cistanche deserticola which had been previously proven to possess anti-osteoporotic activity previously. Currently, it is still unknown whether 6-AA plays a crucial role on the anti-osteoporotic effects of C. deserticola. PURPOSE: To elucidate the therapeutic effect and mechanism of 6-AA on osteoporosis by employing an ovariectomized mouse model in vivo and RAW264.7 cells in vitro. METHODS: Sixty female ICR mice were randomly assigned into six groups: sham-operated control group (SHAM, vehicle), ovariectomized model group (OVX, vehicle), positive group (EV, 1 mg/kg/day of estradiol valerate), low dosage (10 mg/kg/day of 6-AA), medium dosage (20 mg/kg/day of 6-AA) and high dosage (40 mg/kg/day of 6-AA) treatment groups. All substances were administered daily by intragastric gavage. After 12 weeks of intervention, trabecular bone microarchitecture was estimated and bone biomechanics were determined. Bone formation and resorption factors were determined by using the corresponding Elisa kits. The related proteins and metabolites were estimated by using western-blot and metabolomics techniques. RESULTS: OVX mice demonstrated significant atrophy of the uterine and vagina, declined biomechanical parameters such as flexural strength and maximum load, deteriorated trabecular bone microarchitecture such as decreased BMD, BMC, TMC, TMD, BVF, Tb. N, and Tb. Th and increased Tb. Sp, as well as increased bone resorption factors such as TRAP, cathepsin K, and DPD, all after 12 weeks of ovariectomy operation. Following administration of 6-AA to OVX mice, parameters related to the bone microarchitecture, bone resorption activities as well as biomechanical properties were all significantly improved. Meanwhile, the levels of NF-κB, NFATc1, RANK, RANKL and TRAF6 were significantly downregulated, while OPG, PI3K and AKT were upregulated after 6-AA intervention. This indicates that, 6-AA could prevent bone resorption by regulating the RANKL/RANK/OPG mediated NF-κB and PI3K/AKT pathways. Furthermore, 26 different metabolites corresponding to 25 metabolic pathways were identified, and 5 of which were related to the formation of osteoporosis. Interestingly, 23 abnormal metabolites were recovered after 6-AA treatment. CONCLUSION: Our results revealed the significant anti-osteoporotic effects of 6-AA on ovariectomized mice which were probably exerted via suppression of osteoclast formation and bone resorption.

Zinc supplements and bone health: The role of the RANKL-RANK axis as a therapeutic target.

BACKGROUND: To this day, empirical data suggests that zinc has important roles in matrix synthesis, bone turnover, and mineralization and its beneficial effects on bone could be mediated through different mechanisms. The influence of zinc on bone turnover could be facilitated via regulating RANKL/RANK/OPG pathway in bone tissue. Therefore, the aim of the study was to conduct a review to investigate the possible effect of the zinc mediated bone remodeling via RANKL/RANK/OPG pathway. METHODS: A comprehensive systematic search was performed in MEDLINE/PubMed, Cochrane Library, SCOPUS, and Google Scholar to explore the studies investigating the effect of zinc as a bone remodeling factor via RANKL/RANK/OPG pathway regulation. Subsequently, the details of the pathway and the impact of zinc supplements on RANKL/RANK/OPG pathway regulation were discussed. RESULTS: The pathway could play an important role in bone remodeling and any imbalance between RANKL/RANK/OPG components could lead to extreme bone resorption. Although the outcomes of some studies are equivocal, it is evident that zinc possesses protective properties against bone loss by regulating the RANKL/RANK/OPG pathway. There are several experiments where zinc supplementation resulted in upregulation of OPG expression or decreases RANKL level. However, the results of some studies oppose this. CONCLUSION: It is likely that sufficient zinc intake will elicit positive effects on bone health by RANKL/RANK/OPG regulation. Although the outcomes of a few studies are equivocal, it seems that zinc can exert the protective properties against bone loss by suppressing osteoclastogenesis via downregulation of RANKL/RANK. Additionally, there are several experiments where zinc supplementation resulted in upregulation of OPG expression. However, the results of limited studies oppose this. Therefore, aside from the positive role zinc possesses in preserving bone mass, further effects of zinc in RANKL/RANK/OPG system requires further animal/human studies.

Histochemical examination of the effects of high-dose 1,25(OH)2D3 on bone remodeling in young growing rats.

Vitamin D has an anabolic effect on bone developmental processes and is involved in maintaining skeletal integrity. In recent years, pediatric cases of vitamin D intoxication have attracted attention. Therefore, the aim of this study was to investigate the influence of long-term administration of physiologically-high-dose calcitriol (1,25(OH)2D3) on bone remodeling in young developing rats. Neonatal rats received once-daily subcutaneous injection of calcitriol (250 ng/kg body weight), or PBS only as a control, for 3 weeks. At 1, 2 and 4 weeks' post-administration, rats were sacrificed and fixed by transcardial perfusion with 4 % paraformaldehyde, following which tibiae were extracted for histochemical analysis. Compared with the control group, the number of tartrate-resistant acid phosphatase- and Cathepsin K-positive osteoclasts were significantly increased, and the expression of alkaline phosphatase in osteoblasts was decreased in trabecular bone of rats administered high-dose 1,25(OH)2D3, leading to decreased trabecular bone volume. In addition, the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) was increased, while that of osteoprotegerin was weaker in osteoblasts in the experimental group compared with the control group. Moreover, there was weaker immunoreactivity for EphrinB2 in osteoclasts and EphB4 in osteoblasts of trabecular bone in the experimental group compared with the control group. These findings suggest that long-term use of physiologically-high dose calcitriol may result in bone loss through RANKL/RANK/osteoprotegerin and EphrinB2-EphB4 signaling pathways, and that these negative effects could continue after drug withdrawal. Therefore, optimal limits for vitamin D administration need to be established for children and adolescents.