Abstract
Bone formation and regeneration is a multistep complex process crucially determined by the formation of blood vessels in the growth plate region. This is preceded by the expression of growth factors, notably the vascular endothelial growth factor (VEGF), secreted by osteogenic cells, as well as the corresponding response of endothelial cells, although the exact mechanisms remain to be clarified. Thereby, coordinated coupling between osteogenesis and angiogenesis is initiated and sustained. The precise interplay of these two fundamental processes is crucial during times of rapid bone growth or fracture repair in adults. Deviations in this balance might lead to pathologic conditions such as osteoarthritis and ectopic bone formation. Besides VEGF, the recently discovered important regulatory and modifying functions of microRNAs also support this key mechanism. These comprise two principal categories of microRNAs that were identified with specific functions in bone formation (osteomiRs) and/or angiogenesis (angiomiRs). However, as hypoxia is a major driving force behind bone angiogenesis, a third group involved in this process is represented by hypoxia-inducible microRNAs (hypoxamiRs). This review was focused on the identification of microRNAs that were found to have an active role in osteogenesis as well as angiogenesis to date that were termed “CouplingmiRs (CPLGmiRs)”. Outlined representatives therefore represent microRNAs that already have been associated with an active role in osteogenic-angiogenic coupling or are presumed to have its potential. Elucidation of the molecular mechanisms governing bone angiogenesis are of great relevance for improving therapeutic options in bone regeneration, tissue-engineering, and the treatment of bone-related diseases.
Highlights
The replacement of large bone defects and the availability of adequate tissue-engineered bone remains a major clinical challenge
Bone angiogenesis is mainly governed by a spectrum of transcription factors and growth factors which have been mostly elaborated for endochondral ossification so far [23,24]
endothelial cells (ECs) respond by an angiocrine release of NOGGIN, an antagonist of the bone morphogenetic protein (BMP) pathway that stimulates the maturation of hypertrophic chondrocytes expressing vascular endothelial growth factor (VEGF) in the growth plate
Summary
The replacement of large bone defects and the availability of adequate tissue-engineered bone remains a major clinical challenge. Elucidating the wide orchestrating variety of signal pathways and stimuli linking angiogenesis and bone formation on the molecular level is of great interest In this context, the gained information will yield improved bone replacement in fracture healing, or prevention of bone loss in osteoporosis and therapeutically-induced reparative angiogenesis. Intramembranous ossification, in contrast, denominates the process of establishing flat bones where condensed MSCs directly differentiate into osteoblasts, forming an ossification center This pathway leads to the formation of craniofacial, calvarial, and clavicle bones [10]. Recent in vitro experiments in transgenic mice demonstrated that this task is accomplished by a specialized type of blood vessel, i.e., the so-called H-type that is present in long bones [17] This underlines the fact that, comparable to other organs, the acquisition and maintenance of specialized properties by endothelial cells (ECs) is very important for the functional homeostasis in bone. The genetic program of bone angiogenesis needs reactivation during callus formation in fracture healing, which represents a complex process that has not yet been fully elucidated [22]
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