Transforming Growth Factor Beta Family: Insight into the Role of Growth Factors in Regulation of Fracture Healing Biology and Potential Clinical Applications

Poniatowski, Łukasz A.; Wojdasiewicz, Piotr; Gasik, Robert; Szukiewicz, Dariusz

doi:10.1155/2015/137823

Cited by 219 publications

(179 citation statements)

References 231 publications

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“…The ability of macrophages to favorably modulate these processes is dependent on their polarized state, especially in diseased tissue (19,9,17) . M2-like-macrophages play critical roles in inflammation resolution by secreting anti-inflammatory cytokines including IL-10, TGF-β that helps in tissue repair (38,39) and by secreting growth factors (40,41) that induces arteriogenesis and angiogenesis. Based on these functions, it is well accepted that increased M2-like-macrophages are beneficial for the recovery of ischemic-muscle (20,19) .…”

Section: Discussionmentioning

confidence: 99%

A MicroRNA93–Interferon Regulatory Factor-9–Immunoresponsive Gene-1–Itaconic Acid Pathway Modulates M2-Like Macrophage Polarization to Revascularize Ischemic Muscle

et al. 2017

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Background Currently no therapies exist for treating, and improving outcomes in patients with severe peripheral arterial disease (PAD). MicroRNA93 (miR93) has been shown to favorably modulate angiogenesis and reduce tissue loss in genetic PAD models. However, the cell specific function, downstream mechanisms or signaling involved in miR93 mediated ischemic muscle neovascularization is not clear. Macrophages were best known to modulate arteriogenic response in PAD and the extent of arteriogenic response induced by macrophages is dependent on greater M2 to M1-activation/polarization state. In the current study, we identified a novel mechanism by which miR93 regulates macrophage-polarization to promote angiogenesis and arteriogenesis to revascularize ischemic muscle in experimental-PAD. Methods In vitro (macrophages, endothelial cells, skeletal muscle cells under normal and hypoxia serum starvation (HSS) conditions) and in vivo experiments in preclinical-PAD models (unilateral femoral artery ligation and resection)) were conducted to examine the role of miR93-interferon regulatory factor-9 (IRF9)-immune responsive gene-1 (IRG1)-itaconic acid pathway in macrophage-polarization, angiogenesis, arteriogenesis and perfusion recovery. Results In vivo, compared to wild type (WT) controls, miR106b-93-25 cluster deficient mice (miR106b-93-25−/−) showed decreased angiogenesis and arteriogenesis correlating with increased M1-like-macrophages following experimental-PAD. Intra-muscular delivery of miR93 in miR106b-93-25−/− PAD mice increased angiogenesis, arteriogenesis, the extent of perfusion which correlated with more M2-like-macrophages in the proximal and distal hind-limb muscles. In vitro, miR93 promotes and sustains M2-like-polarization even under M1-like-polarizing conditions (HSS). Delivery of bone marrow derived macrophages from miR106b-93-25−/− to WT ischemic-muscle decreased angiogenesis, arteriogenesis and perfusion, while transfer of wild-type macrophages to miR106b-93-25−/− had the opposite effect. Systematic analysis of top-differentially upregulated genes from RNA-sequencing between miR106b-93-25−/− and WT ischemic-muscle showed that miR93 regulates IRG1 function to modulate itaconic acid production and macrophage-polarization. 3′UTR luciferase-assays performed to determine whether IRG1 is a direct target of miR93 revealed that IRG1 is not a miR93 target but IRF9 that can regulate IRG1-expression is a miR93 target. In vitro, increased expression of IRF9, IRG1 and itaconic acid treatment significantly decreased endothelial angiogenic potential. Conclusion We conclude that miR93 inhibits IRF9 to decrease IRG1-itaconic acid production to induce M2-like-polarization in ischemic muscle to enhance angiogenesis, arteriogenesis and perfusion recovery in experimental-PAD.

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Section: Discussionmentioning

confidence: 99%

A MicroRNA93–Interferon Regulatory Factor-9–Immunoresponsive Gene-1–Itaconic Acid Pathway Modulates M2-Like Macrophage Polarization to Revascularize Ischemic Muscle

et al. 2017

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“…After bone fracture and formation of hematoma, the expression of TFG-β increases at the fracture site and continues to be expressed throughout the remodeling phase (Patil et al, 2011, Poniatowski et al, 2015). TFG-β plays a key role in the differentiation and formation of both cartilage and bone tissue by enabling the cellular activities of MSCs, fibroblasts, chondrocytes, osteoblasts and also inhibiting osteoclastic activity (Patil et al, 2011, Narine et al, 2006).…”

Section: Growth Factorsmentioning

confidence: 99%

Bone fracture healing in mechanobiological modeling: A review of principles and methods

et al. 2017

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Bone fracture is a very common body injury. The healing process is physiologically complex, involving both biological and mechanical aspects. Following a fracture, cell migration, cell/tissue differentiation, tissue synthesis, and cytokine and growth factor release occur, regulated by the mechanical environment. Over the past decade, bone healing simulation and modeling has been employed to understand its details and mechanisms, to investigate specific clinical questions, and to design healing strategies. The goal of this effort is to review the history and the most recent work in bone healing simulations with an emphasis on both biological and mechanical properties. Therefore, we provide a brief review of the biology of bone fracture repair, followed by an outline of the key growth factors and mechanical factors influencing it. We then compare different methodologies of bone healing simulation, including conceptual modeling (qualitative modeling of bone healing to understand the general mechanisms), biological modeling (considering only the biological factors and processes), and mechanobiological modeling (considering both biological aspects and mechanical environment). Finally we evaluate different components and clinical applications of bone healing simulation such as mechanical stimuli, phases of bone healing, and angiogenesis.

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“…IL-6 stimulates angiogenesis and vascular endothelial growth factor (VEGF) expression and also induces osteoblast and osteoclast differentiation 4 . Release of TGF-b from damaged tissue is chemotactic for mesenchymal stem cells (MSCs) and immune cells and lowers the local pH, which enhances the release of PDGF, VEGF, bone morphogenetic protein-2 (BMP-2), and other growth factors 11 .…”

Section: Inflammation Phasementioning

confidence: 99%

“…Bone morphogenetic proteins (BMPs) are growth factors from the TGF-b superfamily 10,11 . BMPs are chemotactic for MSCs and stimulate the differentiation of MSCs and endothelial progenitor cells involved in angiogenesis 29 .…”

Section: Progenitor Cells and Growth Factorsmentioning

confidence: 99%

The Biological Basis for Nonunions

Brinker

O’Connor

2016

JBJS Rev

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Fracture nonunion is a failure of the biological processes of fracture-healing. Critical cellular events in fracture-healing include the inflammatory response, differentiation and proliferation of progenitor cells, formation of fibrocartilage callus, angiogenesis and subsequent mineralization of the callus, vascular union (restoration of normal medullary circulation), and conversion of woven bone to lamellar bone. All critical events are closely regulated and coordinated by numerous cytokines and growth factors, which are expressed in complex spatial and temporal patterns throughout the repair process. At all phases of fracture-healing, poor cellular and metabolic capacity (e.g., chronic disease), excessive instability, and poor vascularity inhibit cellular responses and healing. Many biological treatments to prevent or treat nonunions are emerging in clinical use, including stem-cell and bone-marrow-aspirate preparations, various progenitor cells and growth factors (e.g., recombinant human bone morphogenetic proteins), and gene therapy.

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Transforming Growth Factor Beta Family: Insight into the Role of Growth Factors in Regulation of Fracture Healing Biology and Potential Clinical Applications

Cited by 219 publications

References 231 publications

A MicroRNA93–Interferon Regulatory Factor-9–Immunoresponsive Gene-1–Itaconic Acid Pathway Modulates M2-Like Macrophage Polarization to Revascularize Ischemic Muscle

A MicroRNA93–Interferon Regulatory Factor-9–Immunoresponsive Gene-1–Itaconic Acid Pathway Modulates M2-Like Macrophage Polarization to Revascularize Ischemic Muscle

Bone fracture healing in mechanobiological modeling: A review of principles and methods

The Biological Basis for Nonunions

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