From the skin to the bone: Pro-osteoclastogenesis inflammatory march

Up to 30% of psoriasis (Ps) patients develop psoriatic arthritis (PsA): in approximately 80% of cases, arthritis follows Ps in a mean period of 10 years. Pro-inflammatory mediators involved in the pathogenesis of both disease, including interleukin (IL)-33, osteopontin (OPN) and tumor necrosis factor (TNF)-α are increased in the synovium as well as in the skin and contribute to osteoclastogenesis and bone erosion. The aim of this study was to assess the ability of pro-inflammatory mediators such as IL-33, OPN and TNF-α to induce skin prompted osteoclastogenesis. Ex vivo skin organ cultures from healthy donor were stimulated with IL-33, OPN, TNF-α and gene expression of RANKL, IL-6, IL-33, OPN, TNF-α, ST2L, OPG, IL-4, IL-13 and IL-10 was analyzed. Culture supernatants were harvested and used to stimulate healthy donor PBMCs. After 15 days, we performed osteoclasts identification through tartrate resistant acid phosphatase (TRAP) staining and osteoclasts activity assessment through TRAF6, NFATC1 and Cathepsin K gene expression. Our results showed that pro-osteoclastogenesis mediators RANKL, IL-6, IL-33, OPN and TNF-α were overexpressed in ex vivo skin organ cultures stimulated with recombinant IL-33, OPN and TNF-α in a time, but not dose, dependent manner. Conversely, anti-osteoclastogenesis factors such as OPG, IL-4, IL-13 and IL-10 were downregulated respect to unstimulated skin. Osteoclasts overdifferentiated when healthy PBMCs were cultured with supernatants from stimulated skin. Similarly the activation markers of mature osteoclasts, TRAF6, NFATC1 and Cathepsin K, were enhanced. Our results suggest the possibility of a “pro-osteoclastogenesis march” induced by cutaneous pro-inflammatory mediators.