Diminished bone regeneration after debridement of posttraumatic osteomyelitis is accompanied by altered cytokine levels, elevated B cell activity, and increased osteoclast activity

Abstract

Osteomyelitis is a frequent consequence of open fractures thus representing a common bone infection with subsequent alteration of bone regeneration. Impaired bone homeostasis provokes serious variations in the bone remodeling process, thereby involving multiple inflammatory cytokines to activate bone healing. Our previously established mouse model of posttraumatic osteomyelitis provides the chance to study regulation of selected cytokines after surgical debridement of osteomyelitis thus illustrating the course of initial infectious recovery. An inflammatory cytokine array revealed specifically upregulated cytokines in debrided animals after bone infection, that were verified by Western blot analysis, identifying increased levels of CCL2, CCL3, and CXCL2. Increased osteoclastogenesis after debridement of osteomyelitis was demonstrated by Calcitonin-receptor and RANKL detection via immunohistochemical and -fluorescence stainings. The substantial protein analysis was complemented by uncovering diminished osteogenesis and proliferation in debrided group, tracking Osteocalcin, RUNX2, and PCNA expression. Interestingly TNF-α expression seemed to have no effect on altered bone regeneration after bone infection. Additional flow cytometry analysis proved elevated B cell activity, subsequently increased osteoclast activity and accelerated bone resorption. Based on the variety of severely altered cytokines, we propose a RANKL-dependent osteoclastogenesis after debridement of osteomyelitis coinciding with elevated B cells and simultaneously decreased osteogenesis. A comprehensive understanding of these mechanisms provides new therapeutic options of osteomyelitis cure and is of great importance in prospective medical treatment. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2425-2434, 2017.

Lysostaphin and BMP-2 co-delivery reduces S. aureus infection and regenerates critical-sized segmental bone defects

“…They are also involved in the recruitment of neutrophils and macrophages from bone marrow, thereby promoting phagocytosis ( 40 ), consistent with the argument that this increase in helper T cells is evidence of a typical adaptive immune response to infection. Other groups have characterized the inflammatory cells present in bone infection sites for a limited number of cell types, such as myeloid-derived suppressor cells (MDSCs) ( 41 – 43 ) and B cells ( 44 ) as well as T cell subsets located in the draining lymph node and spleen ( 45 ). Vidlak and Kielian ( 46 ) have also reported MDSC, monocyte, macrophage, and CD3 + T cell compositions in the context of prosthetic joint infections.…”

Local Wnt3a treatment restores bone regeneration in large osseous defects after surgical debridement of osteomyelitis

“…Especially in bone infections, this is a common problem of orthopedic surgery [ 26 ]. Based on previous studies [ 3 , 4 ], this work aimed to improve bone healing via activation of canonical Wnt-pathway and reveal Wnt-dependent mechanisms of bone formation and resorption related to bone infection.…”

“…Moreover, the bone in the vicinity still shows a dramatically reduced regenerative capacity despite complete absence of bacteria [ 3 ] after sufficient debridement. Accordingly, a further own study could identify an ongoing inflammatory reaction which leads to an upregulation of cytokines and activation of the innate immune system verified by elevated B cells [ 4 ].…”

“…In this context, plenty of mechanisms in bone inflammation have already been postulated, many involving the activation of the receptor activator nuclear factor-κB ligand (RANKL) which induces nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), resulting in osteoclastogenesis [ 7 ]. Our recent work indicated elevated bone resorption after successful debridement of bone infections in mice [ 4 ]. This was mainly caused by an elevated osteoclastogenesis occurring together with an upregulation of RANKL activity.…”

Substantiation Stages of Rehabilitation at the Patients with Metaepiphyseal Osteomyelitis

“…et al [29] study osteomyelitis as a frequent consequence of open fractures thus representing a common bone infection with subsequent alteration of bone regeneration. Impaired bone homeostasis provokes serious variations in the bone remodeling process, thereby involving multiple inflammatory cytokines to activate bone healing.…”