Epigenetic and transcriptional regulation of osteoclastogenesis in the pathogenesis of skeletal diseases: A systematic review.

OBJECTIVES

To identify epigenetic and transcriptional factors controlling osteoclastogenesis (OCG), that have been shown to play a role in the pathogenesis of skeletal diseases.

METHODS

A systematic review was conducted in accordance with the PRISMA guidelines. The PubMed and EMBASE databases were searched up to 30th April 2020; references of included articles and pertinent review articles were also screened to identify eligible studies. Studies were included if they described epigenetic and/or transcriptional regulation of OCG in a specific skeletal disorder, and quantified alterations in OCG by any well-described experimental method. Risk of bias was assessed by a previously described modification of the CAMARADES tool.

RESULTS

The combined searches yielded 2265 records. Out of these, 24 studies investigating 12 different skeletal disorders were included in the review. Osteoporosis, followed by osteopetrosis, was the most commonly evaluated disorder. A total of 22 different epigenetic and transcriptional regulators of OCG were identified; key epigenetic regulators included DNA methylation, histone methylation, histone acetylation, miRNAs and lncRNAs. In majority of the disorders, dysregulated OCG was noted to occur at the stage of formation of committed osteoclast from preosteoclast. Dysregulation the stage of formation of the preosteoclast from late monocyte was noted in rheumatoid arthritis and fracture, whereas dysregulation at stage of formation of late monocyte from early monocyte was noted in osteopetrosis and spondyloarthritis. Quality assessment revealed a high risk of bias in domains pertaining to randomization, allocation concealment, blinding of outcome assessors and determination of sample size.

CONCLUSIONS

A variety of epigenetic and transcriptional factors can result in dysregulated osteoclastogenesis in different skeletal disorders. Dysregulation can occur at any stage; however, the formation of committed osteoclasts from preosteoclasts is the most common target. Although the published literature on this subject seems promising, the overall strength of evidence is limited by the small number of studies evaluating individual skeletal disorders, and also by deficiencies in key aspects of study design.