Fractured Bone Cross Talks With the Immune System and Other Organs via Mirnas

Bone fracture elicits a cascade of responses with the goal of regenerating the bone. Thereby, many messenger molecules are secreted. One class of messengers are microRNAs (miRNAs) that are produced in the cells and secreted mainly via extracellular vesicles. MiRNAs are 20 nucleotide large nucleic acids that inhibit target messenger RNAs (mRNAs). Depending on the concentration the target mRNA can change and one miRNA can inhibit several mRNAs. During fracture healing, different miRNA are up- or down-regulated. They have pivotal roles in osteogenesis and if produced correctly, they support bone regeneration. Some of the miRNAs play also a role in the immune response. In the early healing phase, mainly pro-inflammatory miRNAs are secreted, whereas in the course of the healing more anti-inflammatory miRNAs are present. There is also an interaction with other organs. The lung is one of the main organs affected by fracture. It is the first capillary bed encountered by the venous and lymphatic system. MiRNAs that influence lung physiology have been identified originating from the fracture area. However, the lung itself also seems to produce miRNAs that are involved in regulating fracture healing. Thus, pulmonary complications upon fracture healing may be partially also regulated via miRNA. Similar pathways have been recognized for liver-bone and kidney-bone interactions. Furthermore, for an effective bone regeneration, vascularization and innervation are important entities that also need to be activated. Some miRNAs have double or triple action profiles. There are miRNAs that are able to induce vascularization at a very early stage of fracture healing. The same set of miRNAs is also inducing neo-neurogenesis by inducing differentiation of stem cells and activating sprouting and branching axons. With the continuous regenerative processes, finally bone formation is induced. The miRNAs elicit differentiation of stem cells into bone cells. Furthermore, they regulate mineralization and at a final stage even the occurrence of osteoclasts. This scenario would lead to a more optimized bone tissue with all essential tissues present. Thus, miRNA are important moieties that have a cross talk with organs, the immune system and important adjuvant systems such as vasculature and neuronal tissue. Identifying these cross-talk pathways may help to better understand tissue regeneration and eventually also modulate it for improving regeneration.