Research regarding the potency and potential of the fracture hematoma has begun to receive increasing attention. However, currently there is a paucity of relevant literature on the capability and composition of the fracture hematoma. This review briefly summarizes the regenerative fracture healing process and the close interplay between the skeletal and immune systems. The role of immune cells in wound healing is also discussed to clarify their involvement in immunological processes during regeneration. We attempt to describe the current state of knowledge regarding the fracture hematoma as the initial stage of the regenerative process of fracture healing. The review discusses how a better understanding of immune reactions in the hematoma may have implications for bone tissue engineering strategies. We conclude the review by emphasizing how additional investigations of the initial phase of healing will allow us to better differentiate between deleterious and beneficial aspects of inflammation, thereby facilitating improved fracture treatment strategies.

Background An effective immune system, especially during the inflammatory phase, putatively influences the quality and likelihood of bone healing. If and how this is reflected within the initial fracture hematoma is unclear.

Immune cells constantly patrol the body via the bloodstream and migrate into multiple tissues where they face variable and sometimes demanding environmental conditions. Nutrient and oxygen availability can vary during homeostasis, and especially during the course of an immune response, creating a demand for immune cells that are highly metabolically dynamic. As an evolutionary response, immune cells have developed different metabolic programmes to supply them with cellular energy and biomolecules, enabling them to cope with changing and challenging metabolic conditions. In the past 5 years, it has become clear that cellular metabolism affects immune cell function and differentiation, and that disease-specific metabolic configurations might provide an explanation for the dysfunctional immune responses seen in rheumatic diseases. This Review outlines the metabolic challenges faced by immune cells in states of homeostasis and inflammation, as well as the variety of metabolic configurations utilized by immune cells during differentiation and activation. Changes in cellular metabolism that contribute towards the dysfunctional immune responses seen in rheumatic diseases are also briefly discussed.

Glucocorticoids mediate their therapeutic actions mostly by genomic effects via cytosolic receptors, but some effects are too rapid to be mediated by changes at the genomic level. The detailed mechanisms of these nongenomic actions are still unclear. Membrane-bound glucocorticoid receptors (mGCR) have been suggested to be involved, although their physiological existence in humans so far is hypothetical. For the first time we demonstrate the existence of mGCR on monocytes and B cells obtained from healthy blood donors using high-sensitivity immunofluorescent staining. Immunostimulation with lipopolysaccharide increases the percentage of mGCR-positive monocytes, which can be prevented by inhibiting the secretory pathway. Overexpression of the human glucocorticoid receptor alpha alone is not sufficient to enhance mGCR expression. These in vitro findings are consistent with our clinical observation that in patients with rheumatoid arthritis the frequency of mGCR positive monocytes is increased and positively correlated with disease activity. We conclude that mGCR are 1) indeed physiologically present in healthy blood donors, but remained unidentified by conventional techniques due to their small number per cell and 2) actively up-regulated and transported through the cell after immunostimulation. These receptors may reflect a feedback mechanism of the organism upon immunostimulation and/or play a role in pathogenesis.

The underlying mechanism appears to be dependent on the FGFR and VEGFR signaling cascades and might be mediated by an additional cross-talk with other pathways. STEM CELLS 2007;25:903-910 Disclosure of potential conflicts of interest is found at the end of this article.

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Glucocorticoids (GCs) are effective immunosuppressive agents and mediate welldefined transcriptional effects via GC receptors. There is increasing evidence that GCs also initiate rapid nongenomic signaling events. Using activated human CD4 ؉ lymphocytes and a peptide array containing 1176 different kinase consensus substrates, we generated a comprehensive profile of GC-induced rapid effects on signal transduction. The results show marked early differences in phosphorylation between GC-pretreated cells and control cells, including impaired phosphorylation of p56lck/p59fyn (Lck/Fyn) consensus substrates. Immunoprecipitation and in vitro kinase assays reveal rapid GC-induced down-modulation of Lck and Fyn kinases using SAM68 (Src IntroductionGlucocorticoids (GCs) are widely used therapeutically for immunosuppression. GC action is mediated through the intracellular GC receptor (GR), present in the cytosol of T cells. In the inactive state of the receptor, GRs are associated with heat shock proteins, which act as chaperones. Upon GC binding this complex dissociates, and the activated GR translocates into the nucleus where it binds to specific DNA motifs (glucocorticoid-responsive elements) and to transcription factors such as activator protein 1 (AP1) and nuclear factor B (NFB), thereby regulating the expression of a number of genes involved in the immunologic process. 1-3 Through regulation of gene expression, GCs reduce the production of proinflammatory mediators, including cytokines (interleukin 1 [IL-1], IL-2, tumor necrosis factor-␣ [TNF-␣], interferon ␥ [IFN-␥], etc), prostaglandins, and nitric oxide. Moreover, GCs inhibit the expression of adhesion molecules and may induce death of T cells. [4][5][6] However, the phenomenon of rapid GC-induced effects in cellular systems occurring within minutes is unlikely explained by the classic GR-mediated mechanism. [7][8][9][10][11][12][13][14][15][16][17][18] The underlying mechanisms of rapid nongenomic GC-dependent immunosuppression remain to be elucidated.Among the earliest recognizable events after T-cell receptor (TCR) stimulation are the activation of p56lck (Lck) and p59fyn (Fyn), resulting in TCR phosphorylation on tyrosine residues within immunoreceptor tyrosine-based activation motifs. 19 Lck and Fyn, members of the Src (pp60c-src) family of tyrosine kinases, are expressed in T cells and are critically involved in TCR-mediated signal transduction. [20][21][22][23] Lck and Fyn have been shown to associate with the TCR complex, and the cellular organization of these kinases is well coordinated and essential for efficient TCR signaling. [24][25][26][27][28] Lck binds to the CD4 or CD8 coreceptor, whereas Fyn is known to associate with CD3. [29][30][31] Alternatively, Lck and Fyn can also physically interact with the CD3 and CD4 coreceptors, respectively, but these interactions are weak. The TCR-CD4 association largely determines the quality of TCR signaling, Lck being the critical mediator. 32,33 As a subsequent step, ZAP70 (-associated protein 70) tyrosine kina...

Glucocorticoids regulate fundamental processes of the human body and control cellular functions such as cell metabolism, growth, differentiation, and apoptosis. Moreover, endogenous glucocorticoids link the endocrine and immune system and ensure the correct function of inflammatory events during tissue repair, regeneration, and pathogen elimination via genomic and rapid non-genomic pathways. Due to their strong immunosuppressive, anti-inflammatory and anti-allergic effects on immune cells, tissues and organs, glucocorticoids significantly improve the quality of life of many patients suffering from diseases caused by a dysregulated immune system. Despite the multitude and seriousness of glucocorticoid-related adverse events including diabetes mellitus, osteoporosis and infections, these agents remain indispensable, representing the most powerful, and cost-effective drugs in the treatment of a wide range of rheumatic diseases. These include rheumatoid arthritis, vasculitis, and connective tissue diseases, as well as many other pathological conditions of the immune system. Depending on the therapeutically affected cell type, glucocorticoid actions strongly vary among different diseases. While immune responses always represent complex reactions involving different cells and cellular processes, specific immune cell populations with key responsibilities driving the pathological mechanisms can be identified for certain autoimmune diseases. In this review, we will focus on the mechanisms of action of glucocorticoids on various leukocyte populations, exemplarily portraying different autoimmune diseases as heterogeneous targets of glucocorticoid actions: (i) Abnormalities in the innate immune response play a crucial role in the initiation and perpetuation of giant cell arteritis (GCA). (ii) Specific types of CD4+ T helper (Th) lymphocytes, namely Th1 and Th17 cells, represent important players in the establishment and course of rheumatoid arthritis (RA), whereas (iii) B cells have emerged as central players in systemic lupus erythematosus (SLE). (iv) Allergic reactions are mainly triggered by several different cytokines released by activated Th2 lymphocytes. Using these examples, we aim to illustrate the versatile modulating effects of glucocorticoids on the immune system. In contrast, in the treatment of lymphoproliferative disorders the pro-apoptotic action of glucocorticoids prevails, but their mechanisms differ depending on the type of cancer. Therefore, we will also give a brief insight into the current knowledge of the mode of glucocorticoid action in oncological treatment focusing on leukemia.