Regulation of melatonin and nutrients in the process of bone and cartilage regeneration with exosomes and microRNAs: a systematic review

Introduction: Bone diseases comprise a large group of common diseases, including fractures, osteoporosis, and osteoarthritis that affect a large number of individuals. Without intervention, the prevalence of osteopenia is projected to increase to 64.3 million Americans and that of osteoporosis to 11.9 million by the year 2030. Melatonin exerts numerous physiological effects, including the induction of anti-inflammatory and antioxidants, resetting circadian rhythms, and promoting wound healing and tissue regeneration, participating in the maintenance and regenerative processes of bones and cartilage. Objective: A systematic review was carried out to present the state of the art of melatonin regulation, mesenchymal stem cells, exosomes, microRNAs, and nutrients in the bone regeneration process. Methods: The systematic review rules (PRISMA) were followed. The search was carried out from January to March 2025 in the Scopus, Embase, PubMed, Science Direct, Scielo, and Google Scholar databases. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: A total of 138 articles were found. A total of 64 articles were fully evaluated and 32 were included in this systematic review. Considering the Cochrane tool for risk of bias, the overall assessment resulted in 9 studies at high risk of bias and 24 studies that did not meet the GRADE. Most studies showed homogeneity in their results, with I2 =92.8%>50%. The symmetrical funnel plot does not suggest a risk of bias between small sample-size studies. Based on the results, melatonin has important functions in regulating the regenerative activities of mesenchymal stem cells that modulate, together with nutrients, the activities of exosomes and microRNAs in the bone and cartilage regeneration process.