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Melatonin's therapeutic potential has been highly underestimated because its biological functional roles are diverse and relevant mechanisms are complicated. Among the numerous biological activities of melatonin, its regulatory effects on pluripotent mesenchymal stem cells (MSCs), which are found in bone marrow stem cells (BMSCs) and adipose tissue (AD-MSC), have been recently proposed, which has received increasingly more attention in recent studies. Moreover, receptor-dependent and receptor-independent responses to melatonin are identified to occur in these cells by regulating signaling pathways, which drive the commitment and differentiation of MSCs into osteogenic, chondrogenic, or adipogenic lineages. Therefore, the aim of our current review is to summarize the evidence related to the utility of melatonin as a regulatory agent by focusing on its relationship with the differentiation of MSCs. In particular, we aimed to review its roles in promoting osteogenic and chondrogenic differentiation and the relevant signaling cascades involved. Also, the roles that melatonin and, particularly, its receptors play in these processes are highlighted., (© 2018 Wiley Periodicals, Inc.)

Background: Destructive erosion of bone or osteolysis is a major complication of inflammatory conditions such as rheumatoid arthritis (RA), periodontal disease, and periprosthetic osteolysis. Natural plant-derived products have received recent attention as potential therapeutic and preventative drugs in human disease., Methods: The effect of Angelica sinensis (AS) extract on RANKL-induced osteoclast differentiation was examined in this study. The osteoclast precursor cell line bone marrow macrophages (BMMs) was cultured and stimulated with RANKL followed by treatment with AS at several doses. Gene expression profiles of c-Fos, c-Jun, NFATc1, TRAP, and OSCAR were sequentially evaluated., Results: AS extract inhibited RANKL-mediated osteoclast differentiation in BMMs in a dose-dependent manner without any evidence of cytotoxicity. AS extract strongly inhibited p38, ERK, JNK, p65 phosphorylation and I-κB degradation in RANKL-stimulated BMMs. AS extract also inhibited the mRNA expression of c-Fos, c-Jun, NFATc1, TRAP, and OSCAR in RANKL-treated BMMs. Moreover, RANKL-induced c-Fos, c-Jun and NFATc1 protein expression was suppressed by AS extract., Conclusions: These results collectively suggested that AS extract demonstrated inhibitory effects on RANKL-mediated osteoclast differentiation in bone marrow macrophages in vitro, indicating that AS may therefore serve as a useful drug in the prevention of bone loss.

The effects of pyrroloquinoline quinine (PQQ) on RANKL-induced osteoclast differentiation and on wear particle-induced osteolysis were examined in this study. PQQ inhibited RANKL-mediated osteoclast differentiation in bone marrow macrophages (BMMs) in a dose-dependent manner without any evidence of cytotoxicity. The mRNA expression of c-Fos, NFATc1, and TRAP in RANKL-treated BMMs was inhibited by PQQ treatment. Moreover, RANKL-induced c-Fos and NFATc1 protein expression was suppressed by PQQ. PQQ additionally inhibited the bone resorptive activity of differentiated osteoclasts. Further a UHMWPE-induced murine calvaria erosion model study was performed to assess the effects of PQQ on wear particle-induced osteolysis in vivo. Mice treated with PQQ demonstrated marked attenuation of bone erosion based on Micro-CT and histologic analysis of calvaria. These results collectively suggested that PQQ demonstrated inhibitory effects on osteoclast differentiation in vitro and may suppress wear particle-induced osteolysis in vivo, indicating that PQQ may therefore serve as a useful drug in the prevention of bone loss.

Psoralidin is a metabolic product from the seed of psoraleacorylifolia, possessed anti-inflammatory and immunomodulatory effects. We speculated that psoralidin might impact osteoclastogenesis and bone loss. By using both in vitro and in vivo studies, we observed psoralidin strongly inhibited RANKL induced osteoclast formation during preosteoclast cultures, suggesting that it acts on osteoclast precursors to inhibit RANKL/RANK signaling. At the molecular level, by using MAPKs specific inhibitors (U-0126, SB-203580 and SP-600125) we demonstrated that psoralidin markedly abrogated the phosphorylation of p38, ERK, JNK. Moreover, the RANKL induced NF-κB/p65 phosphorylation and I-κB degradation were significantly inhibited by psoralidin. Further, psoralidin significantly suppressed osteoclastogenesis marker genes of TRAP, Cathepsin K and OSCAR. These were accompanied by the decreased expression of c-Fos and NFATc1 transcription factors. Consistent with in vitro results, our in vivo and serologic studies showed psoralidin inhibited lipopolysaccharide induced bone resorption by suppressing the inflammatory cytokines: TNF-α and IL-6 expression, as well as the ratio of RNAKL : OPG. These results collectively suggested that psoralidin could represent a novel therapeutic strategy for osteoclast-related disorders, such as rheumatoid arthritis and postmenopausal osteoporosis. [ABSTRACT FROM AUTHOR]