Abstract
Diabetes mellitus is a main risk factor for delayed fracture healing and fracture non-unions. Successful fracture healing requires stimuli from different immune cells, known to be affected in diabetics. Especially, application of mononuclear cells has been proposed to promote wound and fracture healing. Thus, aim was to investigate the effect of pre-/diabetic conditions on mononuclear cell functions essential to promote osteoprogenitor cell function. We here show that pre-/diabetic conditions suppress the expression of chemokines, e.g., CCL2 and CCL8 in osteoprogenitor cells. The associated MCP-1 and MCP-2 were significantly reduced in serum of diabetics. Both MCPs chemoattract mononuclear THP-1 cells. Migration of these cells is suppressed under hyperglycemic conditions, proposing that less mononuclear cells invade the site of fracture in diabetics. Further, we show that the composition of cytokines secreted by mononuclear cells strongly differ between diabetics and controls. Similar is seen in THP-1 cells cultured under hyperinsulinemia or hyperglycemia. The altered secretome reduces the positive effect of the THP-1 cell conditioned medium on migration of osteoprogenitor cells. In summary, our data support that factors secreted by mononuclear cells may support fracture healing by promoting migration of osteoprogenitor cells but suggest that this effect might be reduced in diabetics.
Highlights
With approximately 440 million patients reported in 2019, type 2 diabetes mellitus (T2DM) is the metabolic disorder with the highest worldwide prevalence and incidence.Estimations from the International Diabetes Federation (IDF) indicate that this number will increase to 665 million within the 25 years
THP-1 cell conditioned medium favors migration of osteoprogenitor cells and SCP-1 cells—an effect partly attributed to the secreted TGF-β [21]
We analyzed the role of peripheral blood mononuclear cells (PBMCs) for the migration of osteoprogenitor cells and SCP-1 cells with regard to diabetic conditions
Summary
With approximately 440 million patients reported in 2019, type 2 diabetes mellitus (T2DM) is the metabolic disorder with the highest worldwide prevalence and incidence. Estimations from the International Diabetes Federation (IDF) indicate that this number will increase to 665 million within the 25 years. At risk are elderly, where the prevalence of T2DM increases up to 20% [1]. There is evidence that pre-diabetics already have an altered bone quality and an increased fracture risk [2]. Associated diabetic bone diseases rapidly develop, e.g., diabetic foot syndrome or a Charcot-osteoarthropathy, which affects almost 20% of all diabetics within the first 5 years of the disease [3], often (~20%) resulting in an amputation of the affected limb [4]. T2DM patients often have an increased bone mineral density (BMD) [5,6] with a significantly increased risk for fractures.
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