TLR4-mediated calvarial bone repair: investigating its role and potential use for regenerative medicine

摘要

Abstract: Injuries to the craniofacial skeleton have a tremendous economical and social impact on our healthcare system and society. Presently, clinical management of craniofacial trauma remains highly challenging and various efforts have been undertaken to develop and improve existing therapies for craniofacial reconstruction. Among these efforts, mounting evidence has demonstrated that inflammation is among the first events to determine fracture healing outcome. Thus, understanding how inflammation affects bone healing and subsequently modulating inflammation to enhance bone regeneration has become a promising strategy. Toll-like receptor 4 (TLR4) is a member of TLR family that is central to inflammation by virtue of its involvement in host defense for microbial infection as well as tissue regeneration. As such, TLR4 is a potential candidate for investigation and subsequent immune modulation. This work utilized various knockout (KO) mouse models for TLR4 and its associated inflammatory mediators as tools to study the role of inflammation in calvarial bone healing in the absence or presence of bone grafts. In the absence of bone graft, a similar accelerated phenotype was observed between MyD88 KO mice and DC-TLR4 KO (TLR4 depleted in dendritic cells) mice, indicating that dendritic cell expression of TLR4-mediated MyD88 signaling was detrimental for calvarial bone healing. In addition, TLR4 depletion in myeloid cells also resulted in accelerated bone healing via enhanced osteoclastogenesis within a calvarial defect model. However, in the presence of bone graft, inhibited bone healing and decreased osteoclast-mediated graft remodeling was observed in TLR4 KO mice or when TLR4 signaling was locally inhibited, establishing an important and novel role of TLR4 in graft-based bone repair. Taken together, these data demonstrate that TLR4 signaling and its pathway mediators play an important regulatory role in osteoclastogenesis, highlighting a potential opportunity in which appropriate modulation of TLR4 signaling can be used to initiate early healing in bone defects or assist in bone graft-mediated therapy to improve clinical outcomes.