Boon and Bane of Inflammation in Bone Tissue Regeneration and Its Link with Angiogenesis

Abstract

Delayed healing or nonhealing of bone is an important clinical concern. Although bone, one of the two tissues with scar-free healing capacity, heals in most cases, healing is delayed in more than 10% of clinical cases. Treatment of such delayed healing condition is often painful, risky, time consuming, and expensive. Tissue healing is a multistage regenerative process involving complex and well-orchestrated steps, which are initiated in response to injury. At best, these steps lead to scar-free tissue formation. At the onset of healing, during the inflammatory phase, stationary and attracted macrophages and other immune cells at the fracture site release cytokines in response to injury. This initial reaction to injury is followed by the recruitment, proliferation, and differentiation of mesenchymal stromal cells, synthesis of extracellular matrix proteins, angiogenesis, and finally tissue remodeling. Failure to heal is often associated with poor revascularization. Since blood vessels mediate the transport of circulating cells, oxygen, nutrients, and waste products, they appear essential for successful healing. The strategy of endogenous regeneration in a tissue such as bone is interesting to analyze since it may represent a blueprint of successful tissue formation. This review highlights the interdependency of the time cascades of inflammation, angiogenesis, and tissue regeneration. A better understanding of these inter-relations is mandatory to early identify patients at risk as well as to overcome critical clinical conditions that limit healing. Instead of purely tolerating the inflammatory phase, modulations of inflammation (immunomodulation) might represent a valid therapeutic strategy to enhance angiogenesis and foster later phases of tissue regeneration.

Modeling the effects of inflammation in bone fracture healing

“…The inflammation is characterized by high concentration levels of inflammatory cytokines (pro-inflammatory cytokines) and the invasion of different cell types including macrophages and MSCs [15]. Removal of debris and decreases of inflammatory cytokines levels is the first step of fracture healing [13].…”

“…However, it is not an easy and always a successful process [14]. Indeed in some unfavorable conditions the regenerative cascade fails with approximately 10% of fractures resulting in nonunion [15]. Furthermore, the risk of impaired healing increases with bone diseases, age, and severe traumas [8].…”

“…In particular, macrophages and mesenchymal stem cells (MSCs) have been discovered to be decisive for controlling inflammation by cleaning up debris, releasing anti-inflammatory cytokines, and suppressing inflammatory immune cells functions, respectively [15,7]. However, the exact mechanisms and functions of the immune cells present at the fracture site are still not completely understood [15]. High concentration of inflammatory cytokines leads to increase bone resorption and suppresses bone formation [10].…”

“…Prolonged and chronic inflammation results in delay or nonunion healing [8]. For successful bone healing, the participation of immune cells in the healing process must be brief and well regulated [15].…”

Local induction of inflammation affects bone formation

“…After injury, the initial inflammatory phase is essential for optimal fracture healing to occur, as this triggers a complex interaction between infiltrating immune cells, resident cells and bone progenitor cells (Cho et al, 2002;Gerstenfeld et al, 2003b;Kon et al, 2001;Mountziaris et al, 2011). During this phase, proinflammatory cytokines such as TNF-α, IL-1, IL-6 and IL-17 act together with BMPs and other transforming growth factor family members to induce processes leading to repair and restoration (Cho et al, 2002;Claes et al, 2012;Geusens et al, 2013;Nam et al, 2012;Rundle et al, 2006;Schmidt-Bleek et al, 2015;Yang et al, 2007). Several of these cytokines have stimulatory effects on the osteogenic differentiation of mesenchymal stem cells (MSCs) in vitro Glass et al, 2011;Mountziaris et al, 2011;Ono et al, 2016).…”