Therefore, cells trapped in the hematoma have to switch towards an anaerobic energy supply. The use of the remaining glucose in glycolysis to produce adenosine triphosphate ATP , the energy molecule of the cellular metabolism, without the consecutive citrate cycle, results in lactate, an acid that consecutively lowers the pH value during the initial healing phase. Simultaneously, the sodium and potassium concentrations rise. These conditions present a milieu that is difficult for some cells, such as progenitor cells [ 86 ].
However, innate immune cells are well equipped to deal with these conditions and thus can be seen as the first responders to an injury. They express a range of cytokines that attract scavenger cells to clear the detritus that ensued upon tissue disruption and also direct the cells needed for the regenerative process towards the injury side. They readily switch from an aerobic energy supply towards an anaerobic and are often activated upon injury. Not only macrophages but also some T cell subsets are the most important actors during this first response [ 87 , 88 ].
The swift up-regulation of a proinflammatory reaction upon injury activates immune cells, which are capable to withstand the unfavorable environment and initiate the healing cascade through a very specific and highly controlled release of cytokines. For this process to succeed, effective anti-inflammatory signaling has to begin to terminate the initial proinflammatory reaction.
During this initial phase, the track for a successful healing is thus determined, and it becomes apparent that a skewed first reaction leads to a delayed healing by consecutively retarding the following healing steps. The interdependency of the immune and skeletal system indicates that there is a change in the interaction as the immune system changes with the advancement of age.
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More and more lymphocytes encounter their antigens and the library of known pathogens enlarges. Elderly people with a longer exposure time to antigens thus are prone to experience delayed healing. Mice, a common laboratory animal to investigate bone healing, are mostly kept under sterile conditions.
If bone healing is compared between sterile raised mice and those exposed mice, our group could show that the regenerative capacity was reduced [ 91 , 93 ]. This is an important aspect that should be kept in mind during future research questions, which are analyzed in mice.
Nonsteroidal anti-inflammatory drugs NSAIDs offer pain relief and are commonly used also on fracture patients. As the name already indicates, these selective cyclooxygenase-2 COX-2 inhibitors have anti-inflammatory functions. After reviewing the importance of the initial inflammatory reaction, the question arises whether this pain medication could delay fracture healing or not. The effect, however, depends on the dose and time frame of application and seems to be more pronounced in older nonselective anti—COX-2 agents [ 99 ]. Clinically, NSAIDs are a valuable alternative to opioids painkillers directly addressing the nervous system and still remain in use also in fracture patients for short-term pain relief.
Several diseases have also been reported to delay bone healing through a changed immune response. A weakened immune response in diabetic patients results in a dampened chemotactic function and defective macrophage activity—two factors that are needed in a successful bone healing cascade [ ]. A systemic disease with a high impact on the immune system is human immunodeficiency virus HIV , and these patients have a bone phenotype with a high prevalence of osteoporosis and fragility fractures [ ]. The impact on fracture healing, however, is unclear and difficult to determine due to the highly active antiretroviral therapy that these patients receive [ , ].peresdylan.tk
International Conference on Osteoimmunology: Interactions of the Immune and Skeletal Systems
Transplant patients receiving severe immune suppressive medication also show a higher risk for fractures and delayed healing outcomes. In contrast to these examples — where the immune system is weakened — conditions where a patient has a heightened immune answer or is already in a chronic proinflammatory systemic state, such as rheumatoid and arthritis patients, the prolonged proinflammatory reaction can result in delays in fracture healing [ — ].
However, this could help in the future to stratify patients who would benefit from an immune modulatory intervention to prevent a delay in fracture healing. This would especially be true in elderly patients because being bed-ridden for longer periods of time enhances frailty considerably. In fracture healing, immune cells from the innate immune system and from the adaptive immune system are involved with specific and essential roles.
Main cell types of the adaptive immunity are B and T cells with highly specific antigen receptors. Another important aspect of the adaptive immune system is its memory that enables its fast reaction towards recurring pathogen invasion. Adaptive immune cells can be activated not only through their antigen receptors, but also probably more important for the bone healing process through signals released by the innate immune system.
From the innate immune system, especially macrophages have been in the current focus of osteoimmunology. Macrophages are an important part of the innate immune system; they are among the first responders in case of an injury. Not only do they prevent pathogen invasion, but they also help in clearing ensuing cell debris [ ]. However, their role in bone healing is even more complex and even today we have not yet unraveled their participation completely.
Tissue-resident macrophages have been determined as key players in the orchestration of the recovery process towards a re-establishment of tissue integrity [ ]. It was only in that it was recovered that macrophages are capable of a phenotype change from a proinflammatory type towards a prohealing phenotype [ ]. The proinflammatory phenotype is named M1 or classically activated macrophage, and the second phenotype is termed M2 or alternatively activated macrophage. It turned out that the M2 population is more divers and therefore subclassifications have been introduced: M2a anti-inflammatory , M2b immune-regulatory and M2c remodeling [ ].
In bone healing, the prominent macrophage phenotype during the initial phase is M1. Upon attenuating of the proinflammatory phase, the macrophage phenotype changes towards the M2 phenotype [ 77 ]. In a proof of concept study in mice, we were able to show that an induction of the M2 phenotype early in the fracture healing cascade can enhance bone healing [ 77 ].
The T cell population is highly divers and probably pleiotropic as well as interchangeable. Among the T cells, there seem to be subpopulations supporting the fracture healing process and also other subpopulations, which have negative effects on the healing process.
Mice with an increased percentage of regulatory T cells showed higher bone mass and decreased bone resorption when compared to wild type mice [ , ]. Regulatory T cells support osteoblast differentiation and have a negative impact on osteoclast differentiation and function [ ]. In a skull defect model in mice, it was possible to enhance bone healing through the addition of regulatory T cells in combination with applied autologous bone graft [ ].
The lead cytokine expressed by Th17 T helper 17 is IL The dual effect of IL on osteoclasts and osteoblasts has been mentioned before. Psoriasis has two manifestations, one in skin psoriasis vulgaris and one in bone psoriasis arthritis , and the immune modulatory treatment shows positive results in both [ ]. IL is necessary for stabilization, survival and proliferation of Th17 cells [ ]. For example, a cytokine neutralizing antibody against the p40 subunit of IL inhibiting Th17 differentiation and survival, which in consequence lowers IL concentrations, underwent clinical trials [ , ].
A direct crosstalk between activated T cells and bone-forming cells can be assumed during the healing process. These cells accumulate in the fracture hematoma due to their tissue homing qualities and they occur in higher numbers in patients experiencing a delayed healing [ 91 ]. In the clinical setting, the recognition of a delayed or missing bone healing is so far only possible when these healing disturbances become visible in X-ray or computed tomography evaluations of the fractured bone.
An early identification of patients at risk of a delayed or disturbed fracture healing is still missing. Not only the interaction of the skeletal and immune system in fracture healing is not well understood so far, the immune reaction in itself is also still not unraveled.
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Aside from the complexity of the cytokine pattern guiding the regenerative process, the plasticity of the immune cells is still a vast challenge: M1 macrophage phenotype changing towards M2, Th1 changing towards Th2 response, regulatory T cells changing into Th17 cells and vice versa, to mention only a few aspects that still have to be understood. First approaches have been successful in influencing the fracture treatment through immune modulation NSAIDs or IL neutralization antibodies but the possibilities are far from being exploited.
A stratification of patients can help to decide, which treatment is optimal for which patient, especially with respect to the current immune status of these patients. With the numbers of delayed healing fracture patients still vastly unknown and possibly massively underestimated, and the demographic prognostic of a substantial increase in the elderly population during the next years, the need for further treatment options is rising together with the necessity of enhanced basic research in the field of osteoimmunology.
We like to acknowledge Dr. Hanna Schell for providing histological images to visualize bone anatomy. Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Help us write another book on this subject and reach those readers. Login to your personal dashboard for more detailed statistics on your publications. Edited by Alessandro Rozim Zorzi.
We are IntechOpen, the world's leading publisher of Open Access books. Built by scientists, for scientists. Our readership spans scientists, professors, researchers, librarians, and students, as well as business professionals. Downloaded: The conference will bring together leading international scientists from both fields to interact so that new collaboration can develop and more rapid progress in understanding the relationships between these fields can be achieved.
Osteoimmunology: interactions of the bone and immune system.
Short talks will be selected from abstracts from the international community. This conference will have a format to provide an environment of maximum interaction and interchange through lectures, posters, and open discussion. Have doubts regarding this product? Post your question. Safe and Secure Payments. Easy returns. Osteoclasts, the cells that resorb bone, are important cellular mediators of skeletal homeostasis and are derived from hematopoietic precursors that also give rise to immune cells.
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In addition, numerous cytokines, which were first shown to regulate immune cell function, are now known to regulate bone cells and influence skeletal health. Conversely, cells in the osteoblast lineage and their cytokines are critical for the development of the hematopoietic stem cell niche and the normal development of the hematopoietic and immune cell lineages. Up until recently, scientists involved in immune or bone cell research rarely interacted in a significant way because each discipline developed independently and, for the most part, has remained separate.
The fundamental hypothesis of the organizers of this conference is that progress in the field of osteoimmunology, which is the study of the interactions of bone, hematopoietic and immune cells in health and disease, will be delayed unless better communication is established between bone biologists, hematologist and immunologists.