Differential regulation of blood vessel formation between standard and delayed bone healing

Lienau, Jasmin; Schmidt‐Bleek, Katharina; Peters, Anja; Haschke, F.; Duda, Georg N.; Perka, Carsten; Bail, Hermann Josef; Schütze, Norbert; Jakob, Franz; Schell, Hanna

doi:10.1002/jor.20870

Cited by 123 publications

(126 citation statements)

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“…RUNX1 (runt-related transcription factor 1) expression predominates in early hematopoietic cells (Medina et al 2011) and is important for hematopoietic stem and progenitor cell proliferation (Friedman 2009). VWF (von Willebrandt factor) is a marker protein for endothelial cells (Lienau et al 2009) and HMOX1 (heme oxygenase-1) has pro-angiogenic and anti-inflammatory effects and is important for the recruitment of endothelial progenitor cells in neovasculatory processes (Dulak et al 2008). The presence of progenitor cells and angiogenic markers can therefore be reporters for an ongoing revasculatory process which has to be seen as the first step in fracture healing.…”

Section: Introductionmentioning

confidence: 98%

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Inflammatory phase of bone healing initiates the regenerative healing cascade

et al. 2011

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Bone healing commences with an inflammatory reaction which initiates the regenerative healing process leading in the end to reconstitution of bone. An unbalanced immune reaction during this early bone healing phase is hypothesized to disturb the healing cascade in a way that delays bone healing and jeopardizes the successful healing outcome. The immune cell composition and expression pattern of angiogenic factors were investigated in a sheep bone osteotomy model and compared to a mechanically-induced impaired/delayed bone healing group. In the impaired/delayed healing group, significantly higher T cell percentages were present in the bone hematoma and the bone marrow adjacent to the osteotomy gap when compared to the normal healing group. This was mirrored in the higher cytotoxic T cell percentage detected under delayed bone healing conditions indicating longer pro-inflammatory processes. The highly activated periosteum adjourning the osteotomy gap showed lower expression of hematopoietic stem cell markers and angiogenic factors such as heme oxygenase and vascular endothelial growth factor. This indicates a deferred revascularization of the injured area due to ongoing pro-inflammatory processes in the delayed healing group. Results from this study suggest that there are unfavorable immune cells and factors participating in the initial healing phase. In conclusion, identifying beneficial aspects may lead to promising therapeutical approaches that might benefit further by eliminating the unfavorable factors.

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Section: Introductionmentioning

confidence: 98%

“…Angiogenesis plays a pivotal role during bone healing (Harper and Klagsbrun 1999;Lienau et al 2009). The formation of new blood vessels is promoted after fracture to regain oxygen homeostasis, deliver nutrients, remove waste products, and provide cells and mediators.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory phase of bone healing initiates the regenerative healing cascade

et al. 2011

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“…A healing fracture and the immune system responsible for inflammatory processes share numerous signaling and regulatory mechanisms [13,45]. As the initial phase of the bone-healing cascade, inflammation plays a pivotal role in the process of fracture repair during which an early scaffold of the callus is formed [15,29]. It triggers synthesis of the extracellular matrix, stimulates revascularization, and recruits mesenchymal stem cells (MSCs) and other progenitor cells [15,25].…”

Section: Introductionmentioning

confidence: 99%

Defective Bone Repair in C57Bl6 Mice With Acute Systemic Inflammation

Behrends

Hui

Gao

et al. 2017

Clinical Orthopaedics &Amp; Related Research

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Background Bone repair is initiated with a local inflammatory response to injury. The presence of systemic inflammation impairs bone healing and often leads to malunion, although the underlying mechanisms remain poorly defined. Our research objective was to use a mouse model of cortical bone repair to determine the effect of systemic inflammation on cells in the bone healing microenvironment. Question/Purposes (1) Does systemic inflammation, induced by lipopolysaccharide (LPS) administration affect the quantity and quality of regenerating bone in primary bone healing? (2) Does systemic inflammation alter vascularization and the number or activity of inflammatory cells, osteoblasts, and osteoclasts in the bone healing microenvironment? Methods Cortical defects were drilled in the femoral diaphysis of female and male C57BL/6 mice aged 5 to 9 months that were treated with daily systemic injections of LPS or physiologic saline as control for 7 days. Mice were euthanized at 1 week (Control, n = 7; LPS, n = 8), 2 weeks (Control, n = 7; LPS, n = 8), and 6 weeks (Control, n = 9; LPS, n = 8) after surgery. The quantity (bone volume per tissue volume [BV/TV]) and microarchitecture (trabecular separation and thickness, porosity) of bone in the defect were quantified with time using microCT. The presence or activity of vascular endothelial cells (CD34), macrophages (F4/80), osteoblasts (alkaline phosphatase [ALP]), and osteoclasts (tartrate-resistant acid phosphatase [TRAP]) were evaluated using histochemical analyses.The institution of one or more of the authors (JEH, PAM) has received, during the study period, funding from the Fonds de recherche Santé Québec. The remaining authors certify that neither he or she, nor a member of his or her immediate family, has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. Results Only one of eight defects was bridged completely 6 weeks after surgery in LPS-injected mouse bones compared with seven of nine defects in the control mouse bones (odds ratio [OR], 0.04; 95% CI, 0.003-0.560; p = 0.007). The decrease in cortical bone in LPS-treated mice was reflected in reduced BV/TV (21% ± 4% vs 39% ± 10%; p\0.01), increased trabecular separation (240 ± 36 lm vs 171 ± 29 lm; p \ 0.01), decreased trabecular thickness (81 ± 18 lm vs 110 ± 22 lm; p = 0.02), and porosity (79% ± 4% vs 60% ± 10%; p \ 0.01) at 6 weeks postoperative. Defective healing was accompanied by decreased CD34 (1.1 ± 0.6 vs 3.4 ± 0.9; p\0.01), ALP (1.9 ± 0.9 vs 6.1 ± 3.2; p = 0.03), and TRAP (3.3 ± 4.7 vs 7.2 ± 4.0; p = 0.01) activity, and increased F4/80 (13 ± 2.6 vs 6.8 ± 1.7; p \ 0.01) activity at 2 weeks postoperative. Conclusion The results indicate that LPS-induced systemic inflammation reduced the amount and impaired the quality of bone regenerated in mouse femurs. The effects were associated with impaired revascularization, decreased bone turnover by osteoblasts...

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“…No cartilage remains; 28 days: remodeling phase. Histological samples stained with Movat Pentachrome: bone = yellow; bone marrow =purple; cartilage = blue-green, muscle = orange; connective tissue = light blue [2,4,6,15,[34][35][36][37][38][39][40][41][42][43]. Periost has been carefully elevated from the bone and was stained with hematoxylin eosin.…”

Section: Resultsmentioning

confidence: 99%