Callus mineralization and maturation are delayed during fracture healing in interleukin-6 knockout mice

Yang, Xu; Ricciardi, Benjamin F.; Hernandez-Soria, Alexia; Shi, Yu; Camacho, Nancy P.; Bostrom, Mathias P.

doi:10.1016/j.bone.2007.07.022

Cited by 257 publications

(191 citation statements)

References 46 publications

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“…IL-6 signaling, therefore, appears to play a role in the early stages of fracture healing, but its role diminishes over time (Yang et al, 2007). An earlier study showed that IL-6 expressed in hDPCs following stimulation with lipopolysaccharide (Tokuda et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Mucus of Achatina fulica stimulates mineralization and inflammatoryresponse in dental pulp cells

Kantawong

Thaweenan²,

Mungkala³

et al. 2016

Turk J Biol

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IntroductionDental and oral diseases are major concerns in Thailand, affecting the country's health system. Everyone, at any age, is at risk of losing teeth. Tooth loss can lead to many health problems, including difficulty chewing, which increases the risk of poor nutrition. In addition, tooth loss leaves a large gap, leading to plaque accumulation that can cause periodontal disease. Moreover, the remaining teeth start to shift in an attempt to fill in the gap, leading to misalignment of teeth. Losing teeth may also affect personality, including a loss of confidence that may affect work or social activities. Restoration, with dentures or dental implants, is needed to replace the missing teeth.Current research has focused on dental and bone implants capable of promoting cell differentiation Xavier Acasigua et al., 2014;Naddeo et al., 2015). Cells isolated from tooth pulp contain odontoblasts, fibroblasts, immune cells, and undifferentiated mesenchymal cells called dental pulp stem cells (DPSCs). These findings may lead to restoration using dental pulp cells (DPCs), together with dental implants, to replace lost teeth. Various research groups have proposed the possibility of producing bioactive dental implants by adding natural products, such as natural hydroxyapatite/ zircon (Karamian et al., 2014), plant products (Varoni et al., 2012), or herbal extracts (Wang et al., 2012), to dental materials.Snails have been used in medicine since ancient times. Until the late 19th century, the synthetic peptide ziconotide (SNXIII), which is found in the venom of Conus magus, was used as a painkiller following approval by the United States Food and Drug Administration (Bonnemain, 2005). According to reports, snails contain several medically useful substances, including mytimacinlike antimicrobial peptides, which are exclusively found in the mucus of giant African snails (Zhong et al., 2013). In addition, lectin, which acts as an antimicrobial, is also present in the mucus of giant African snails (Ito et al., 2011). High-performance liquid chromatography was used to determine the amount of allantoin and glycolic Abstract: Dental pulp tissue contains stem cells that can be isolated and used for regenerative medicine in tooth restoration or autologous transplantation. The aim of this study was to observe the mineralization and gene expression in dental pulp cells (DPCs) following treatment with snail mucus. Snail mucus was collected from adult Achatina fulica and processed as a dry powder by the freeze-drying technique. The mucus powder was dissolved in a culture medium at a concentration of 15 µg/mL. DPCs were prepared by the outgrowth technique and cultured in a 6-well plate at a density of 5 × 10 4 cells per well. A mucus-supplemented medium (15 µg/mL) was added to each well. Cell culture was maintained for 3 weeks. The results of Alizarin Red S staining indicated that the DPCs cultured in a medium supplemented with snail mucus showed a higher number of mineralized nodules as compared with the control group cultured in a norm...

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Section: Discussionmentioning

confidence: 99%

Mucus of Achatina fulica stimulates mineralization and inflammatoryresponse in dental pulp cells

Kantawong

Thaweenan²,

Mungkala³

et al. 2016

Turk J Biol

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“…35 If this model is valid, one would expect that IL-6 ablation decreases RANK ligand production, reducing but not eradicating osteoclastogensis. Yang et al 24 cited decreased BMD, increased cartilage content, and reduced osteoclast counts in fracture calluses derived from IL-6 knockouts at 2-weeks postfracture; by 4 weeks, differences had resolved. This histologic observation of delayed callus maturation was reflected in our data.…”

Section: Discussionmentioning

confidence: 99%

“…21 Murine models of fracture healing have shown elevations in IL-6 during intramembranous callus remodeling 22 as well as secondary bone remodeling associated with endochondral ossification. 23 Recently, Yang et al 24 provided insight into the effects of IL-6 on fracture healing, noting an impairment of osteoclastogenesis. Similarly, Axmann et al 25 showed that abrogating IL-6 receptor function also reduced osteoclast counts in a model of inflammatory (RA) bone erosion.…”

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confidence: 99%

Effects of Interleukin‐6 Ablation on Fracture Healing in Mice

Wallace

Cooney

Englund

et al. 2011

Journal Orthopaedic Research

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This study examined the impact of an interleukin-6 (IL-6) knockout on fracture healing in terms of histological and biomechanical responses. Following IACUC approval, tibial fractures were produced in 4-to 6-week-old IL-6 knockouts (n ¼ 35) and wild-type mice (n ¼ 36) and harvested along with contralateral limbs at 2 and 6 weeks postsurgery. Histology quantified stage of healing, lymphocyte infiltration, TRAPþ cells, and osteocalcin deposition. Bend testing established maximum load and stiffness. Based on normality assessments, Mann-Whitney U or independent t-tests were used for data analysis using a p-value threshold of 0.05. Stage of healing, lymphocyte infiltration, and osteocalcin deposition were similar for all time points (p ! 0.243). TRAPþ cell counts were reduced approximately 10-fold in the knockout at 2 weeks (p ¼ 0.015) but were similar at 6 weeks (p ¼ 0.689). Force-to-failure in knockouts was approximately 40% that of wild-type mice at 2 weeks (p ¼ 0.040) but similar at 6 weeks (p ¼ 0.735). Knockout bone was about 25% less stiff at 2 weeks but approximately 60% stiffer at 6 weeks (p ! 0.110). The absence of IL-6 during early fracture healing significantly reduced osteoclastogenesis and impaired callus strength. By 6 weeks, most histological and biomechanical parameters were similar to fractures in wild-type bone. Keywords: cytokines; interleukin-6; fracture healing Inflammation is a key component to both wound and bony healing responses. Leukocytosis is a part of this phenomenom and is integral to fracture healing.1-3 In particular, neutrophil infiltration is apparently allied with establishing chondrogenesis, a sentinel component of endochondral ossification. 4Cytokines are also involved in regulating the healing response. IL-1 plays a prominent role in the early response to injury, 5-7 exerting both proliferative [7][8][9][10] and catabolic effects. 11 It also stimulates the expression of IL-6 by osteoblasts. [12][13][14] There is a substantial body of research that suggest that IL-6 exerts effects on bone homeostasis and repair. IL-6 stimulates production of RANK ligand by osteoblasts which, in turn, catalyzes the formation of osteoclasts from peripheral blood monocytes.15 It was shown to induce differentiation of pre-osteoblasts, [16][17][18] inhibit nodule formation in bone culture, 19 and induce cathepsin B production by osteoblasts.20 During distraction osteogenesis, IL-6 is produced by osteoblasts, hemopoietic cells, and cells associated with the lengthening callus. 21 Murine models of fracture healing have shown elevations in IL-6 during intramembranous callus remodeling 22 as well as secondary bone remodeling associated with endochondral ossification. 23 Recently, Yang et al. 24 provided insight into the effects of IL-6 on fracture healing, noting an impairment of osteoclastogenesis. Similarly, Axmann et al. 25 showed that abrogating IL-6 receptor function also reduced osteoclast counts in a model of inflammatory (RA) bone erosion.Given the importance of the inflammatory response ...

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“…32 In a mouse model of fracture, interleukin-1 and TNF were localized predominately to macrophages and inflammatory cells in the marrow and periosteum adjacent to fracture sites. 31 In mouse models of fracture in which recruitment of inflammatory macrophages 28 or inflammatory cytokine signaling [33][34][35] was compromised through germline genetic alterations, there were prolonged negative impacts on fracture healing. These data support the theory that either reduction of inflammatory macrophages (without specific assessment of resident macrophages) or diminution of their inflammatory cytokine output from the time of injury compromises fracture 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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Callus mineralization and maturation are delayed during fracture healing in interleukin-6 knockout mice

Cited by 257 publications

References 46 publications

Mucus of Achatina fulica stimulates mineralization and inflammatoryresponse in dental pulp cells

Mucus of Achatina fulica stimulates mineralization and inflammatoryresponse in dental pulp cells

Effects of Interleukin‐6 Ablation on Fracture Healing in Mice

Unraveling macrophage contributions to bone repair

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