Bone Abstracts

The regeneration of traumatized, damaged or lost bone is still a major clinical and socio-economical problem. Bone-tissue engineering approaches involve culturing mesenchymal stem cells (MSCs) on scaffolds, in order to create a 3D microenvironment in which MSCs are able to generate functional tissues and regulate foreign body reaction to implanted construct. Excessive or non-resolving inflammation, characterized by the presence of monocytes, macrophages and giant cells, makes a major contribution to osteolysis and implant failure. In recent years, it has been postulated that one of the mechanisms of MSC action in tissue repair is the modulation of the macrophage-mediated inflammatory response through the secretion of soluble factors. Despite its long-standing association with calcium homeostasis and bone metabolism, accumulating evidence suggests that 1,25(OH)₂D₃ has immunomodulatory effects on cells of the monocyte/macrophage lineage. In this context, we investigated the effect of 1,25(OH)₂D₃ on the production of soluble factors involved in fracture healing in a co-culture model of MSCs and macrophages. To this aim, human MSCs and TPA differentiated THP1 cells were either cultured separately or co-cultured in the presence or absence of 10 nM 1,25(OH)₂D₃. Treatment with 1,25(OH)₂D₃ reduced TNFα–IL-6, MCP1, PGE₂, and VEGF release from macrophages. IL6 and VEGF secretion from MSCs increased in response to 1,25(OH)₂D₃ while MCP1 levels decreased. Compared to isolated macrophages, lower levels of TNFα and RANTES were detected in co-cultures with MSCs while IL6, MCP1, PGE₂, and VEGF secretion increased. Among these factors, TNFα, IL6, and PGE₂ were regulated by 1,25(OH)₂D₃ in MSC/macrophage co-cultures. Taking together, these data suggest that 1,25(OH)₂D₃ is involved in the modulation of the local complex interplay of soluble factors during tissue regeneration.