Fracture healing under healthy and inflammatory conditions

Claes, Lutz; Recknagel, Stefan; Ignatius, Anita

doi:10.1038/nrrheum.2012.1

Cited by 958 publications

(964 citation statements)

References 118 publications

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“…Experimentally, elevated systemic inflammation due to additional soft-tissue trauma injuries impairs fracture healing, 42,43 confirming that persistence of a proinflammatory environment is one mechanism responsible for detrimental fracture healing. 44 Interestingly, low-dose TNF administered to the fracture site at the time of surgery and 1 day post surgery improved fracture healing in mice, 45 suggesting that TNF, and potentially macrophage activation, has complex dose-and time-dependent outcomes on bone healing.…”

Section: Macrophage Contributions To Inflammation During Fracture Repairmentioning

confidence: 99%

Unraveling macrophage contributions to bone repair

et al. 2013

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Macrophages have reemerged to prominence with widened understanding of their pleiotropic contributions to many biologies and pathologies. This includes clear advances in revealing their importance in wound healing. Here we have focused on the current state of knowledge with respect to bone repair, which has received relatively little scientific attention compared with its soft-tissue counterparts. Our detailed characterization of resident tissue macrophages residing in bone-lining tissues (osteomacs), including their pro-anabolic function, exposed a more prominent role for these cells in bone biology than previously anticipated. Recent studies have confirmed the importance of macrophages in early inflammatory processes that establish the healing cascade after bone fracture. Emerging data support that macrophage influence extends into both anabolic and catabolic phases of repair, suggesting that these cells have prolonged and diverse functions during fracture healing. More research is needed to clarify macrophage phase-specific contributions, temporospatial subpopulation variance and macrophage specific-molecular mediators. There is also clear motivation for determining whether macrophage alterations underlie compromised fracture healing. Overall, there is strong justification to pursue strategies targeting macrophages and/or their products for improving normal bone healing and overcoming failed repair.

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Section: Macrophage Contributions To Inflammation During Fracture Repairmentioning

confidence: 99%

Unraveling macrophage contributions to bone repair

et al. 2013

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“…Thus, it is conceivable that pHe changes in bone may not only affect differentiated cells but also stem cell populations. Indeed, the acidification that usually occurs in the early phases of fracture repair (Claes et al, 2012) has been suggested to be a stress stimulus that can be perceived by stem cells and a driving force for regeneration through the release of growth factors that act on the stem cell fraction to repair bone (Chakkalakal et al, 1994). It has been shown that the hypoxic and thus acidic environment of the bone marrow haematopoietic stem cell niche is essential for the fate of stem cells, thus suggesting an association between local acidosis and stemness of mesenchymal stem cells (Mohyeldin et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

The effect of extracellular acidosis on the behaviour of mesenchymal stem cells in vitro

Massa

Perut

Chano

et al. 2017

eCM

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The stem cell fraction of a cell population is finely tuned by stimuli from the external microenvironment. Among these stimuli, a decrease of extracellular pH (pHe) may occur in a variety of physiological and pathological conditions, including hypoxia and inflammation. In this study, by using bone marrow stem cells and dental pulp stem cells, we provided evidence that extracellular acidosis endows the maintenance of stemness in mesenchymal cells. Indeed, continuous exposure for 21 d to low pHe (6.5-6.8) conditions impaired the osteogenic differentiation of both cell types. Moreover, the exposure to low pHe, for 1 and up to 7 d, induced the expression of stemness-related genes and proteins, drove cells to reside in the quiescent G0 alert state and enhanced their ability to form floating spheres. The pre-conditioning with extracellular acidosis for 7 d did not affect the differentiation potential of dental pulp stem cells since, when the cells were cultured again at physiological pHe, their multilineage potential was almost unmodified.Our data provided evidence of the role of extracellular acidosis as a modulator of the stemness of mesenchymal cells. This condition is commonly found both in systemic and local bone conditions, hence underlining the relevance of this phenomenon for a better comprehension of bone healing and regeneration.

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“…The concerted action of these factors regulates the recruitment and proliferation of multipotent mesenchymal stromal cells (MSC) and osteoblasts, the differentiation of MSC into osteoblasts and chondrocytes as well as angiogenesis to reestablish a sufficient blood supply (2,3). After the formation of primary bone, remodeling leads to the formation of secondary bone, which depicts the original anatomical and functional properties before the fracture (2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

IL-1β Inhibits Human Osteoblast Migration

Hengartner

Fiedler

Ignatius

et al. 2013

Mol Med

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Bone has a high capacity for self-renewal and repair. Prolonged local secretion of interleukin 1β (IL-1β), however, is known to be associated with severe bone loss and delayed fracture healing. Since induction of bone resorption by IL-1β may not sufficiently explain these pathologic processes, we investigated, in vitro, if and how IL-1β affects migration of multipotent mesenchymal stromal cells (MSC) or osteoblasts. We found that homogenous exposure to IL-1β significantly diminished both nondirectional migration and site-directed migration toward the chemotactic factors platelet-derived growth factor (PDGF)-BB and insulinlike growth factor 1 (IGF-1) in osteoblasts. Exposure to a concentration gradient of IL-1β induced an even stronger inhibition of migration and completely abolished the migratory response of osteoblasts toward PDGF-BB, IGF-1, vascular endothelial growth factor A (VEGF-A) and the complement factor C5a. IL-1β induced extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinases (JNK) activation and inhibition of these signaling pathways suggested an involvement in the IL-1β effects on osteoblast migration. In contrast, basal migration of MSC and their migratory activity toward PDGF-BB was found to be unaffected by IL-1β. These results indicate that the presence of IL-1β leads to impaired recruitment of osteoblasts which might influence early stages of fracture healing and could have pathological relevance for bone remodeling in inflammatory bone disease.

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Fracture healing under healthy and inflammatory conditions

Cited by 958 publications

References 118 publications

Unraveling macrophage contributions to bone repair

Unraveling macrophage contributions to bone repair

The effect of extracellular acidosis on the behaviour of mesenchymal stem cells in vitro

IL-1β Inhibits Human Osteoblast Migration

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