Role of melatonin combined with exercise as a switch-like regulator for circadian behavior in advanced osteoarthritic knee

Abstract

Here, we show the role of melatonin combined with or without exercise as a determinant of multicellular behavior in osteoarthritis. We address the relationship between the molecular components governing local circadian clock and changes in the osteoarthritic musculoskeletal axis. Melatonin was injected subcutaneously in animals with advanced knee osteoarthritis (OA) for 4 weeks. Concurrently, moderate treadmill exercise was applied for 30 min/day. Morphometric, histological, and gene/protein-level analyses were performed in the cartilage, synovium, bone, and gastrocnemius muscle. Primary cultured chondrocytes repeatedly exposed to TNF-α were used in an in vitro study. The symptoms of OA include gait disturbance, osteophyte formation, and abnormal metabolism of the extracellular matrix (ECM) of the cartilage. Low-level expression of clock genes was accompanied by aberrant changes in cartilage specimens. Nanomolar doses of melatonin restored the expression of clock-controlled genes and corrected the abnormal chondrocyte phenotype. Melatonin combined with or without exercise prevented periarticular muscle damage as well as cartilage degeneration. But prolonged melatonin administration promoted the proteolytic cleavage of RANKL protein in the synovium, leading to severe subchondral bone erosion. These musculoskeletal changes apparently occurred via the regulation of molecular clock components, suggesting a role of melatonin as a switch-like regulator for the OA phenotype.

Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis

“…Deciphering the underlying mechanisms has revealed that the anti-inflammatory effect of melatonin could be mediated by a SIRT1-dependant inhibition of the NF-kB pathway (Lim et al, 2012 ). Consistent with a role of cartilage clock in OA, low doses of oral melatonin, in association with exercise, was found to concomitantly restore the OA-associated reduced levels of clock-controlled genes and reduce the severity of cartilage damages in a murine model of collagenase-induced OA (Hong et al, 2017 ). This converging body of evidence suggesting that melatonin exerts a protective effect in OA remains however to be consolidated through well-conducted in vitro and in vivo experiments in animal model of OA or in clinical trial, notably with respect to the ambiguous role of SIRT1 in mediating the pro-inflammatory effects of IL-1β or H 2 O 2 in chondrocytes (Guo et al, 2017 ; Hong et al, 2017 ).…”

Circadian Clock: Potential Role in Cartilage Integrity and Disruption

“…Hence, while this review is not a systematic one and may have omitted some contrary research, the bulk of the carefully selected literature implies that the status of a synovial joint can be mediated or moderated by an array of factors including cellular clocks and clock genes within articular cartilage chondrocytes, which seem tissue specific [18] . In turn, circadian rhythms produced by articular cartilage core clock genes can impact the turnover of local as well as adjacent musculoskeletal tissue constituents, while simultaneously impacting the extent and rhythmicity of the master circadian clock, as well as fostering intractable bouts of pain and inflammation (See Table 1 and Figure 1).…”

“…In the interim, the bulk of the presently carefully selected literature clearly shows the status of a synovial joint can be readily mediated or moderated by an array of factors including cellular clocks and clock genes within articular cartilage chondrocytes [22] , which seem tissue specific [18] . In turn, disturbances of circadian rhythms produced by core clock genes can invoke significant health disturbances such as pain and inflammation.…”

Improvement of the Treatment of Chronic Noncalculous Cholecystitis in Patients With Diabetes Mellitus Type 2

“…Однак значення мелатоніну (як ключового гормонального регулятора цир-кадних ритмів) у патогенезі та лікуванні ОА залишається дискусійним. У дослідженнях in vivo та in vitro показано, що в артрозному хрящі мелатонін пригнічує експресію катаболічних медіаторів, медіаторів апоптозу, запобігає пошкодженню навколосуглобових м'язів, хоч під час тривалого застосування провокує ерозування субхондральної кістки [31]. Клінічний досвід застосування екзогенного мелатоніну у хворих на ОА незначний.…”