Bone possesses an innate capacity to regenerate following injury. The majority of bony injuries, when properly treated by re-apposition, heal without a permanent lesion. However, many clinical indications remain that require therapeutic intervention to augment bone regeneration such as large craniomaxillofacial defects, bone degeneration in patients with osteonecrosis, distal tibial fractures and periodontal disease.
Autologous bone grafting is currently the gold standard, but this approach is associated with numerous drawbacks, including donor-site morbidity, the availability of limited grafting material and compromised bone quality in patients with osteoporosis. Therefore, extensive efforts have been made to develop bone regenerative strategies using various combinations of cells growth factors6 and biomaterials. However, only few of these strategies have translated into clinical practice and none of them have become a standard in regenerative medicine.
Efficacy, safety, practical, cost-effectiveness and regulatory issues often prevent the widespread therapeutic use of bone regenerative therapies. In addition, one of the major challenges lies in the limited understanding of the cellular and molecular mechanisms that should be targeted to promote bone regeneration. Especially, understanding and subsequently controlling the immune regulations of bone regeneration could be crucial to improve the effectiveness of bone regenerative therapies.
Commonly, tissue injury and the healing response lead to the release of various endogenous danger signals including Toll-like receptor (TLR) and interleukin-1 receptor, type 1 (IL-1R1) ligands, which modulate the immune microenvironment. These danger signals are involved in the recruitment and the activation of immune cells engaged in host defence. In addition, TLRs and IL-1R1 have been shown to influence the repair process of several tissues.
In this study published in Nature Communications, authors explore the role of TLRs and IL-1R1 during bone regeneration, seeking to design regenerative strategies integrating a control of their signalling. They show that IL-1R1 signalling via the adaptor protein MyD88 negatively regulates bone regeneration, in the mouse.
IL-1β is released at the bone injury site and inhibits the regenerative capacities of mesenchymal stem cells (MSCs). Mechanistically, IL-1R1/MyD88 signalling impairs MSC migration, proliferation and differentiation into osteoblasts, by inhibiting the Akt/GSK-3β/β-catenin pathway.
Furthermore, they propose a MSC delivery system integrating inhibitors of IL-1R1/MyD88 signalling. Using this approach, authors significantly improve MSC-based bone regeneration in a mouse critical size calvarial defect model, demonstrating that this approach may be useful in regenerative medicine applications.
http://www.nature.com/ncomms/2016/160322/ncomms11051/full/ncomms11051.html
Bone regeneration following injury!
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