Melatonin prevents bone destruction in mice with retinoic acid–induced osteoporosis

Abstract

Background The protective effect of melatonin against bone metabolism imbalance in osteoporosis (OP) induced by drugs such as retinoic acid (RA) is unclear. The aim of this study was to explore the role of melatonin in bone destruction based on a mouse model. Methods RA-induced OP model mice were established. To assess the effect of melatonin on these mice, micro-CT was used to characterize the trabecular structure of normal mice and those treated with RA (model), RA + low-dose melatonin (Mlt-L), RA + high-dose melatonin (Mlt-H), and RA + alendronate sodium (positive control). The shape of the trabecular bone, the length and diameter of the femoral head and the height and diameter of vertebra(L1) of each group were also measured and the number of osteoclasts was determined by Tartrate-resistant acid phosphatase (TRACP) staining. Meanwhile, the expression of alkaline phosphatase (ALP) was evaluated by immunohistochemistry assays. The differences between groups in terms of liver and kidney oxidation–related indexes and serum and urinary indicators related to bone metabolism were also analyzed. Furthermore, qRT-PCR and western blotting were used to evaluate the effect of melatonin on osteogenic and osteoclastic differentiation in MC3T3-E1 and RAW264.7 cells, respectively. Results RA induction led to a decrease in the amount and density of trabecular bone, a decrease in the length and diameter of the femur and height, diameter of the vertebra (L1), a decrease in bone mass and density and the expression of ALP, and an increase in the number of osteoclasts. Melatonin treatment alleviated these effects induced by RA, increasing the amount of trabecular bone in OP mice, improving the microstructure of the femur and vertebra(L1) and increasing bone mass bone density and the expression of ALP, as well as decreasing the number of osteoclasts. Additionally, blood and urinary bone metabolism-related indicators showed that melatonin promoted bone formation and inhibited bone resorption. Determination of oxidant and antioxidant biomarkers in the livers and kidneys of the mice revealed that melatonin promoted the antioxidant level and suppressed the level of oxidant molecules in these organs. In vitro, RA promoted osteoclasts and inhibit osteogenesis by increasing oxidative stress levels in the RAW264.7 and MC3T3-E1 cells, but melatonin reversed this effect. Melatonin may, therefore, play a role in the ERK/SMAD and NF-κB pathways. Conclusions Melatonin can alleviate bone loss in RA-induced OP model mice, repair the trabecular microstructure, and promote bone formation. These effects may be related to reducing oxidation levels in vivo and vitro through the ERK/SMAD and NF-κB pathways. Electronic supplementary material The online version of this article (10.1186/s10020-019-0107-0) contains supplementary material, which is available to authorized users.

Melatonin promotes bone marrow mesenchymal stem cell osteogenic differentiation and prevents osteoporosis development through modulating circ_0003865 that sponges miR-3653-3p

“…Importantly, recent studies have shown that MEL promotes bone formation and alleviates bone destruction in a mouse OP model induced by retinoic acid. This effect is mediated by its reduction of oxidant levels and modulation of extracellular signal-regulated kinase and nuclear factor kappa B signaling pathways [13]. Furthermore, MEL maintains BMSC stemness and promotes the osteoblast differentiation and osteogenesis of BMSCs [14][15][16].…”

Melatonin promotes bone marrow mesenchymal stem cell osteogenic differentiation and prevents osteoporosis development through modulating circ_0003865 that sponges miR-3653-3p

“…Importantly, recent studies have shown that MEL promotes bone formation and alleviates bone destruction in a mouse OP model induced by retinoic acid. This effect is mediated by its reduction of oxidant levels and modulation of extracellular signal-regulated kinase and nuclear factor kappa B signaling pathways [13]. Furthermore, MEL maintains BMSCs stemness and promotes the osteoblast differentiation and osteogenesis of BMSCs [14,15,16].…”

Melatonin inhibits RANKL‑induced osteoclastogenesis through the miR‑882/Rev‑erbα axis in Raw264.7 cells

“…Bone homeostasis is maintained through osteogenesis and osteoclastogenesis ( 23 ). Osteoclasts originate via a process of differentiation from hematopoietic stem cells or monocytes ( 24 ).…”