Abstract
Immunologically restricted patients such as those with autoimmune diseases or malignancies often suffer from delayed or insufficient fracture healing. In human fracture hematomas and the surrounding bone marrow obtained from immunologically restricted patients, we analyzed the initial inflammatory phase on cellular and humoral level via flow cytometry and multiplex suspension array. Compared with controls, we demonstrated higher numbers of immune cells like monocytes/macrophages, natural killer T (NKT) cells, and activated T helper cells within the fracture hematomas and/or the surrounding bone marrow. Also, several pro-inflammatory cytokines such as Interleukin (IL)-6 and Tumor necrosis factor α (TNFα), chemokines (e.g., Eotaxin and RANTES), pro-angiogenic factors (e.g., IL-8 and Macrophage migration inhibitory factor: MIF), and regulatory cytokines (e.g., IL-10) were found at higher levels within the fracture hematomas and/or the surrounding bone marrow of immunologically restricted patients when compared to controls. We conclude here that the inflammatory activity on cellular and humoral levels at fracture sites of immunologically restricted patients considerably exceeds that of control patients. The initial inflammatory phase profoundly differs between these patient groups and is probably one of the reasons for prolonged or insufficient fracture healing often occurring within immunologically restricted patients.
Highlights
Patients suffering from disorders which impact their immune function often exhibit delayed or ineffective fracture healing [1,2,3,4,5,6,7,8,9], and sometimes even the development of pseudarthrosis [7,8,9]
Immune cell populations were analyzed within the fracture hematoma (FH) and the surrounding bone marrow (SBM) of immunologically restricted (IR) patients and compared to FH and SBM of controls; the gating strategy is presented in Supplemental Figure 1
The amounts of CD14+ monocytes/macrophages and CD34+ hematopoietic stem and progenitor cells were increased significantly within SBM IR when compared to SBM of controls and numerically within the FH IR when compared to FH of controls (Figure 1A,B)
Summary
Patients suffering from disorders which impact their immune function often exhibit delayed or ineffective fracture healing [1,2,3,4,5,6,7,8,9], and sometimes even the development of pseudarthrosis [7,8,9]. After a trauma which leads to a fracture, a hematoma is formed in the fracture gap This fracture hematoma represents the site of the initial inflammatory phase [11]. Very little is known about these initial processes of fracture healing in patients with restricted immune functions. We have shown that immunologically restricted patients exhibit an inadequate response to bioenergetically adverse conditions like hypoxia which characterize the early milieu within the fracture gap [14]. Both enhanced inflammatory response and inadequate adaptation to hypoxia may lead to the decreased expression of Runt-related transcription factor 2 (RUNX-2) shown in the fracture hematomas of patients with restricted immune functions [14]. RUNX-2 is a transcription factor mediating osteogenesis [15,16,17]
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