Inflammation, fracture and bone repair

Abstract

The reconstitution of lost bone is a subject that is germane to many orthopedic conditions including fractures and non-unions, infection, inflammatory arthritis, osteoporosis, osteonecrosis, metabolic bone disease, tumors, and periprosthetic particle-associated osteolysis. In this regard, the processes of acute and chronic inflammation play an integral role. Acute inflammation is initiated by endogenous or exogenous adverse stimuli, and can become chronic in nature if not resolved by normal homeostatic mechanisms. Dysregulated inflammation leads to increased bone resorption and suppressed bone formation. Crosstalk among inflammatory cells (polymorphonuclear leukocytes and cells of the monocyte-macrophage-osteoclast lineage) and cells related to bone healing (cells of the mesenchymal stem cell-osteoblast lineage and vascular lineage) is essential to the formation, repair and remodeling of bone. In this review, the authors provide a comprehensive summary of the literature related to inflammation and bone repair. Special emphasis is placed on the underlying cellular and molecular mechanisms, and potential interventions that can favorably modulate the outcome of clinical conditions that involve bone repair.

Keywords: Bone repair; Fracture healing; Inflammation; Tissue engineering.

Figure 1. The main factors influencing fracture healing

The so-called diamond concept of fracture healing has been modified to encompass the prominent role of inflammatory cells and their secreted mediators. The importance of osteoprogenitor cells, growth factors, osteoconductive scaffold, blood supply, and the mechanical environment in bone regeneration and successful fracture healing has been well documented. Evidence is accumulating that inflammatory cells and their mediators play an equally important role both in the regulation and dysregulation of fracture healing.

Figure 2. Crosstalk between inflammatory cells and bone progenitor cells

Cells of the monocyte-macrophage-osteoclast and MSC-osteoblast lineages modulate each other. Blue lines/arrows indicate inhibition/promotion of differentiation. Red lines/arrows indicate inhibition/promotion of proliferation. Green arrows indicate promotion of migration. Abbreviations: MSC = mesenchymal stem cell, HSC = hematopoietic stem cell, Runx2 = runt-related transcription factor 2, Osx = osterix, OPG = osteoprotegerin, RANKL = receptor activator of nuclear factor κ-B ligand, M-CSF = macrophage colony stimulating factor, IFN-γ = interferon gamma, TNF-α = tumor necrosis factor α, IL = interleukin, TGF = transforming growth factor, VEGF = vascular endothelial growth factor, MCP-1 = monocyte chemoattractant protein-1, RANTES = regulated on activation, normal T expressed and secreted, and BMP = bone morphogenetic protein.

Figure 3. Clinical opportunities for enhancing bone healing by an inflammatory-centered approach

Normal bone healing and the main cells involved in each stage are represented in the upper row. In the middle row, note the persistence of fibrous callus after inflammatory events in fracture healing in the elderly and non-unions. In the lower row, an endo-osseous implant experiment with a foreign body reaction (FBR) at the interface between host bone and the implant, leading to osseointegration. The exposure of wear debris undermines the osseointegrated implant leading to the re-activation of peri-implant inflammation, chronic inflammation and osteolysis, with subsequent loosening of the implant. Tissue engineering and biotherapies (green dashed line) are potential therapeutic interventions to reverse the adverse biological processes by recapitulating early inflammatory events of normal bone healing in fractures in the elderly, non-unions and early stages of periprosthetic osteolysis, respectively.