Moreover, RANKL is positively regulated by proinflammatory cytokines IL-6, TNF-a, IL-1β, and IL-11, which are released by different cells in an inflammatory microenvironment and sustain further osteoclast formation and activity [50], leading to extensive bone damage in osteo-inflammatory diseases, such as osteoporosis, rheumatoid arthritis, and osteoarthritis [51]. This evidence concerns the gene TNF and osteoarthritis.