Aging plays an important role in the pathogenesis of OA. The risk of cartilage damage increases gradually with increasing age. Evidence exists that inflammation and oxidative damage accelerate the development of OA[5]. Yudoh et al[6] reported that oxidative stress could decrease the replicative potential of chondrocytes, shorten telomere length, and reduce glycosaminoglycan production. Rodriguez et al[7] reported that melatonin could decrease the levels of interleukin-1, tumor necrosis factor-α, and nitric oxide. Results from this study demonstrated that melatonin has anti-inflammatory, antioxidant properties together with the role of anti-aging.
Another line of evidence on melatonin effect on the articular cartilage is derived from studies regarding bone mesenchymal stromal cells. Tan et al[8] reported that in addition to largely secreted by the pineal gland, melatonin has extra origin, as present evidence showing high levels of melatonin in bone marrow of pinealectomized rats. They speculated that melatonin from bone marrow cells is produced by its own synthesis. A previous study has demonstrated that melatonin receptors (MT1, MT2) gene exists in human bone marrow-derived mesenchymal stem cells (BMSCs)[9]. Moreover, melatonin directly affects cartilage tissue and regulates chondrocyte proliferation, apoptosis and endochondral bone activity[10]. Another experimental evidence suggests that BMSCs could produce chondrocytes and repair cartilage defects[11]. Meantime, MSCs incubated with melatonin display a higher expression of basic fibroblast growth factor and hepatocyte growth factor[12]. Hepatocyte growth factor modulates hormonal sensitivity of the chondrocyte during proliferation, differentiation, and/or apoptosis through stimulating mRNA expression of type Ⅱ collagen[13]. Fibroblast growth factor not only promotes the proliferation of chondrocytes, but also induces mesenchymal stem cells to repair cartilage defects[14]. Meantime, up-regulated internal transforming growth factor beta1 (TGF-β1) expression was observed in the melatonin-treated cells. TGF-β1 is one of the anabolic factors associated with cartilage maintenance and appears to be a good candidate for cartilage repair[15]. Taken together, melatonin is involved in cartilage differentiation and regeneration, the antioxidant and anti-inflammatory ability of melatonin not only protects cartilage from injury, but also provides a healthy environment for cartilage repair and regeneration. Melatonin exerts direct effects on chondrocytes. Chondrocyte anabolic synthesis is accomplished by stimulating chondrocytes to produce more cartilage matrix components through the TGF-β1 signal pathway. Therefore, melatonin has a positive effect on damaged articular cartilage.
Intra-articular injection of compound betamethasone, mainly consisting of analgesics and nonsteroidal anti-inflammatory drugs, is a very common and useful pharmacotherapy modality for symptomatic knee osteoarthritis. The compound betamethasone can reduce blood capillary permeability, alleviate hyperemia, improve blood circulation, and inhibit inflammatory infiltration and exudation. In addition, it also can gradually attenuate intercellular substance edema and accelerate metabolism. However, the effects of intra-articular injection of melatonin combined with compound betamethasone have not been studied previously. Currently, clinical studies regarding treatment of articular cartilage damage are mostly based on OA animal models successfully created. Results from this study demonstrated that papain-induced OA models exhibited rough surface of articular cartilage, fibrous layer of cartilage thinning, cluster growth of chondrocytes, which are close to clinical physiopathological changes of OA and consistent with the pathogenesis of OA. Caution should be made to avoid cartilage damage caused by surgery.
Results from this study demonstrated that: (1) treatment of melatonin combined with compound betamethasone greatly attenuated articular cartilage damage compared with the OA and pinealectomy groups, suggesting that melatonin combined with compound betamethasone can inhibit degenerative process of cartilage. (2) Following toluidine blue staining, chondrocytes were better arranged, dispersed chondrocytes and loss of staining were significantly decreased in the treatment group compared with the OA and pinealectomy groups. These indicate that melatonin can promote cartilage repair and regeneration. (3) Serum level of melatonin was highest in the control group, followed by the OA group, and the last pinealectomy group, suggesting that serum level of melatonin is related to degenerative development of OA. Aging is possibly involved in this procedure. With aging, the pineal gland was gradually calcified, leading to decreased melatonin secretion and accelerating chondrocyte degeneration. Accumulative evidence exists that melatonin combined with compound betamethasone is directly or indirectly involved in chondrocyte growth, promotes the repair of damaged cartilage and the regeneration of degenerative cartilage, indicating the antioxidant and anti-aging properties of melatonin and the anti-inflammatory property of compound betamethasone. In addition, melatonin combined with compound betamethasone can provide a healthy environment for protecting cartilage against damage. Besides, melatonin can accelerate chondrocyte anabolic synthesis through creating cartilage matrix components via up-regulating the expression of TGF-β1. All these findings suggest that melatonin plays a significant role in the regeneration of damaged articular cartilage.
The present study was to test the effects of melatonin combined with compound betamethasone on damaged articular cartilage. Results demonstrated that intra-articular injection of melatonin combined with compound betamethasone could reduce articular destruction and promote the repair and regeneration of damaged articular cartilage in rats. However, the side effects and effective dose range are unclear. Moreover, the risk and drawbacks still need a lot of experiments to study. At the same time, these findings of this study were limited, several issues bear further consideration. First, damaged articular cartilages are involved in the modulation of cytokines. Second, pathopoiesis of osteoarthritis is a very complex process. Further complementary studies involving a large number of experiments are warranted to thoroughly understand the effects of melatonin combined with compound betamethasone on damaged articular cartilage.
