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Toll-like receptor 4 mediates the regenerative effects of bone grafts for calvarial bone repair.

ABSTRACT: Craniofacial trauma is difficult to repair and presents a significant burden to the healthcare system. The inflammatory response following bone trauma is critical to initiate healing, serving to recruit inflammatory and progenitor cells and to promote angiogenesis. A role for inflammation in graft-induced bone regeneration has been suggested, but is still not well understood. The current study assessed the impact of Toll-like receptor (TLR4) signaling on calvarial repair in the presence of morselized bone components. Calvarial defects in wild-type and global TLR4(-/-) knockout mouse strains were treated with fractionated bone components in the presence or absence of a TLR4 neutralizing peptide. Defect healing was subsequently evaluated over 28 days by microcomputed tomography and histology. The matrix-enriched fraction of morselized bone stimulated calvarial bone repair comparably with intact bone graft, although the capacity for grafts to induce calvarial bone repair was significantly diminished by inhibition or genetic ablation of TLR4. Overall, our findings suggest that the matrix component of bone graft stimulates calvarial bone repair in a TLR4-dependent manner. These results support the need to better understand the role of inflammation in the design and implementation of strategies to improve bone healing.

SUBMITTER: Wang D

PROVIDER: S-EPMC4394876 | biostudies-other | 2015 Apr

REPOSITORIES: biostudies-other

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Toll-like receptor 4 mediates the regenerative effects of bone grafts for calvarial bone repair.

Wang Dan D Gilbert James R JR Shaw Melissa A MA Shakir Sameer S Losee Joseph E JE Billiar Timothy R TR Cooper Gregory M GM

Tissue engineering. Part A 20150401 7-8

Craniofacial trauma is difficult to repair and presents a significant burden to the healthcare system. The inflammatory response following bone trauma is critical to initiate healing, serving to recruit inflammatory and progenitor cells and to promote angiogenesis. A role for inflammation in graft-induced bone regeneration has been suggested, but is still not well understood. The current study assessed the impact of Toll-like receptor (TLR4) signaling on calvarial repair in the presence of morse ...[more]

PMID: 25603990

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Project description:We previously demonstrated that overexpression of tropomyosin receptor kinase A (TrkA) promotes the survival and Schwann cell-like differentiation of bone marrow stromal stem cells in nerve grafts, thereby enhancing the regeneration and functional recovery of the peripheral nerve. In the present study, we investigated the molecular mechanisms underlying the neuroprotective effects of TrkA in bone marrow stromal stem cells seeded into nerve grafts. Bone marrow stromal stem cells from Sprague-Dawley rats were infected with recombinant lentivirus vector expressing rat TrkA, TrkA-shRNA or the respective control. The cells were then seeded into allogeneic rat acellular nerve allografts for bridging a 1-cm right sciatic nerve defect. Then, 8 weeks after surgery, hematoxylin and eosin staining showed that compared with the control groups, the cells and fibers in the TrkA overexpressing group were more densely and uniformly arranged, whereas they were relatively sparse and arranged in a disordered manner in the TrkA-shRNA group. Western blot assay showed that compared with the control groups, the TrkA overexpressing group had higher expression of the myelin marker, myelin basic protein and the axonal marker neurofilament 200. The TrkA overexpressing group also had higher levels of various signaling molecules, including TrkA, pTrkA (Tyr490), extracellular signal-regulated kinases 1/2 (Erk1/2), pErk1/2 (Thr202/Tyr204), and the anti-apoptotic proteins Bcl-2 and Bcl-xL. In contrast, these proteins were downregulated, while the pro-apoptotic factors Bax and Bad were upregulated, in the TrkA-shRNA group. The levels of the TrkA effectors Akt and pAkt (Ser473) were not different among the groups. These results suggest that TrkA enhances the survival and regenerative capacity of bone marrow stromal stem cells through upregulation of the Erk/Bcl-2 pathway. All procedures were approved by the Animal Ethical and Welfare Committee of Shenzhen University, China in December 2014 (approval No. AEWC-2014-001219).

Dataset Information

Toll-like receptor 4 mediates the regenerative effects of bone grafts for calvarial bone repair.

Publications

Toll-like receptor 4 mediates the regenerative effects of bone grafts for calvarial bone repair.

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