Background Osteoimmunology is an evolving field where the multipotential stromal cells (MSCs) can be considered as an important player linking immune response with bone generation. A group of pro-inflammatory cytokines including IFN-γ, TNF-α, IL-17 and IL-1, has been proven to have a licensing effect on MSCs promoting the immunomodulatory activities of MSCs (1). Importantly, these cytokines can regulate the osteogenic differentiation capability of MSCs and in particular, IL-1 and IL-17 can enhance the MSC osteogenesis as shown in previous in vitro studies (2,3). However, little is known about the role of these cytokine-MSC interactions in the bone-related diseases in humans.
Objectives The main focus of this study was to assess if the immune-dependent licensing process of MSCs could be involved in defective bone regeneration.
Methods We used samples of bone marrow aspirates (n=15) from two groups of traumatic bone fracture patients; normal union and non-union. Bone marrow MSCs were analyzed for the surface expression of the receptors of the pro-inflammatory licensing cytokines using flowcytometry-optimized panels. Additionally, a comparison of the cytokine effect on the proliferation of cultured MSCs was compared between normal union and non-union groups using the cell proliferation XTT test.
Results Interestingly, there were significant lower expression levels of IL-1 receptors 1 and 3 (IL-1R1 and IL-1R3) on non-union MSCs compared to normal-union MSCs (p=0.0478 and p=0.0113 respectively). Furthermore, the surface levels of TNF-αR1 (CD120a) were significantly lesser on non-union MSCs (p=0.0119). There was a clear trend of reduced expression of IL-17 receptors (CD217) on the surface of non-union MSCs, but it was not statistically significant compared to normal-union (p=0.0726). The XTT data showed a significant less proliferation index for IL-1-treated non-union MSCs compared to normal-union MSCs (p=0.0446). Also, a consistent trend of lower proliferation index of non-union MSCs was detected when these cells were treated by IFN-γ, TNF-α or IL-17.
Conclusions Together, the lower levels of the pro-inflammatory cytokine receptors indicated a possible mechanism for a defective response of non-union MSCs to the inflammatory signals (particularly IL-1). Further understating of the impact of immune-MSC interactions on human bone healing and regeneration will help to develop new therapies for musculoskeletal diseases involving osteolytic lesions.
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Acknowledgements This project (no. S-16–132E) was supported by the AO Foundation.
Disclosure of Interest None declared
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