The host immune response to bone biomaterials is vital in determining scaffold fates and bone regeneration outcomes. The nanometer-scale interface of biomaterials, which independently controls ...physical inputs to cells, regulates osteogenic differentiation of stem cells and local immune response. Herein, we fabricated biomimetic hierarchical intrafibrillarly mineralized collagen (HIMC) with a bone-like staggered nanointerface and investigated its immunomodulatory properties and mesenchymal stem cell (MSC) recruitment during endogenous bone regeneration. The acquired HIMC potently induced neo-bone formation by promoting CD68+CD163+ M2 macrophage polarization and CD146+STRO-1+ host MSC recruitment in critical-sized bone defects. Mechanistically, HIMC facilitated M2 macrophage polarization and interleukin (IL)-4 secretion to promote MSC osteogenic differentiation. An anti-IL4 neutralizing antibody significantly reduced M2 macrophage-mediated osteogenic differentiation of MSCs. Moreover, HIMC-loaded-IL-4 implantation into critical-sized mandible defects dramatically enhanced bone regeneration and CD68+CD163+ M2 macrophage polarization. The depletion of monocyte/macrophages by clodronate liposomes significantly impaired bone regeneration by HIMC, but did not affect MSC recruitment. Thus, in emulating natural design, the hierarchical nanointerface possesses the capacity to recruit host MSCs and promote endogenous bone regeneration by immunomodulation of macrophage polarization through IL-4.
Objectives
Mechanical force plays an important role in modulating stem cell fate and behaviours. However, how periodontal ligament stem cells (PDLSCs) perceive mechanical stimulus and transfer it ...into biological signals, and thereby promote alveolar bone remodelling, is unclear.
Materials and Methods
An animal model of force‐induced tooth movement and a compressive force in vitro was used. After force application, tooth movement distance, mesenchymal stem cell and osteoclast number, and proinflammatory cytokine expression were detected in periodontal tissues. Then, rat primary PDLSCs with or without force loading were isolated, and their stem cell characteristics including clonogenicity, proliferation, multipotent differentiation and immunoregulatory properties were evaluated. Under compressive force in vitro, the effects of the ERK signalling pathway on PDLSC characteristics were evaluated by Western blotting.
Results
Mechanical force in vivo induced PDLSC proliferation, which was accompanied with inflammatory cytokine accumulation, osteoclast differentiation and TRPV4 activation; the force‐stimulated PDLSCs showed greater clonogenicity and proliferation, reduced differentiation ability, improved induction of macrophage migration, osteoclast differentiation and proinflammatory factor expression. The biological changes induced by mechanical force could be partially suppressed by TRPV4 inhibition. Mechanistically, force‐induced activation of TRPV4 in PDLSCs regulated osteoclast differentiation by affecting the RANKL/OPG system via ERK signalling.
Conclusions
Taken together, we show here that TRPV4 activation in PDLSCs under mechanical force contributes to changing their stem cell characteristics and modulates bone remodelling during tooth movement.
Mechanical force in vivo induced periodontal ligament stem cell proliferation, which was accompanied with inflammatory cytokine accumulation, osteoclast differentiation and TRPV4 activation. The activation of TRPV4 in PDLSCs under mechanical force contributes to the changes in their stem cell characteristics including clonogenicity, proliferation, multipotent differentiation, and immunoregulation and modulates bone remodelling during tooth movement.
Objectives
Temporomandibular joint osteoarthritis (TMJOA) is approximately twice as prevalent in women than in men. Synoviocytes are believed to play a critical role in joint inflammation. However, ...it is unknown whether synoviocytes from different genders possess sexual dimorphisms that contribute to female‐predominant TMJOA.
Materials and Methods
Freund's complete adjuvant combined with monosodium iodoacetate was used to induce TMJOA in female and male rats. Histologic and radiographic features were used to evaluate TMJOA. The expression of CD68, MCP‐1, iNOS, and IL‐1β was detected by immunohistochemistry and real‐time PCR. Primary fibroblast‐like synoviocytes (FLSs) isolated from the synovial membrane of female and male rats were used for in vitro experiments.
Results
Female rats showed aggravated TMJOA features as compared to male rats. Increased expression of iNOS and IL‐1β was detected in synovial membrane from female TMJOA rats as compared to male rats. Furthermore, greater amounts of CD68‐positive macrophage infiltration and increased MCP‐1 expression around the synovial membrane were detected in female TMJOA rats compared to males. Primary cultured FLSs from female rats showed higher sensitivity to TNF‐α treatment and recruited increased macrophage migration than male FLSs. More important, ovariectomy (OVX) by ablation in female rats repressed the sensitivity of female FLSs to TNF‐α treatment due to the loss of estrogen production. Blockage of the estrogen receptor repressed estrogen‐potentiated TNF‐α‐induced pro‐inflammatory cytokine expression in OVX‐FLSs. Moreover, the injection of estrogen receptor antagonists relieved the cartilage destruction and bone deterioration of TMJOA in female rats.
Conclusion
Estrogen‐sensitized synoviocytes in female rats may contribute to gender differences in the incidence and progression of TMJOA.
Osteoarthritis (OA) is an important subtype of temporomandibular disorders. A simple and reproducible animal model that mimics the histopathologic changes, both in the cartilage and subchondral bone, ...and clinical symptoms of temporomandibular joint osteoarthritis (TMJOA) would help in our understanding of its process and underlying mechanism.
To explore whether injection of monosodium iodoacetate (MIA) into the upper compartment of rat TMJ could induce OA-like lesions.
Female rats were injected with varied doses of MIA into the upper compartment and observed for up to 12 weeks. Histologic, radiographic, behavioral, and molecular changes in the TMJ were evaluated by light and electron microscopy, MicroCT scanning, head withdrawal threshold test, real-time PCR, immunohistochemistry, and TUNEL assay.
The intermediate zone of the disc loosened by 1 day post-MIA injection and thinned thereafter. Injection of an MIA dose of 0.5 mg or higher induced typical OA-like lesions in the TMJ within 4 weeks. Condylar destruction presented in a time-dependent manner, including chondrocyte apoptosis in the early stages, subsequent cartilage matrix disorganization and subchondral bone erosion, fibrosis, subchondral bone sclerosis, and osteophyte formation in the late stages. Nociceptive responses increased in the early stages, corresponding to severe synovitis. Furthermore, chondrocyte apoptosis and an imbalance between anabolism and catabolism of cartilage and subchondral bone might account for the condylar destruction.
Multi-level data demonstrated a reliable and convenient rat model of TMJOA could be induced by MIA injection into the upper compartment. The model might facilitate TMJOA related researches.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Macrophages play a major role in joint inflammation. Estrogen is involved in rheumatoid arthritis and temporomandibular disorders. However, the underlying mechanism is still unclear. This study was ...done to verify and test how estrogen affects M1/M2-like macrophage polarization and then contributes to joint inflammation. Female rats were ovariectomized and treated with increasing doses of 17β-estradiol for 10 d and then intra-articularly injected with CFA to induce temporomandibular joint (TMJ) inflammation. The polarization of macrophages and expression of cadherin-11 was evaluated at 24 h after the induction of TMJ inflammation and after blocking cadherin-11 or estrogen receptors. NR8383 macrophages were treated with estradiol and TNF-α, with or without blocking cadherin-11 or estrogen receptors, to evaluate the expression of the M1/M2-like macrophage-associated genes. We found that estradiol increased the infiltration of macrophages with a proinflammatory M1-like predominant profile in the synovium of inflamed TMJ. In addition, estradiol dose-dependently upregulated the expressions of the M1-associated proinflammatory factor inducible NO synthase (iNOS) but repressed the expressions of the M2-associated genes IL-10 and arginase in NR8383 macrophages. Furthermore, estradiol mainly promoted cadherin-11 expression in M1-like macrophages of inflamed TMJ. By contrast, blockage of cadherin-11 concurrently reversed estradiol-potentiated M1-like macrophage activation and TMJ inflammation, as well as reversed TNF-α-induced induction of inducible NO synthase and NO in NR8383 macrophages. The blocking of estrogen receptors reversed estradiol-potentiated M1-like macrophage activation and cadherin-11 expression. These results suggested that estradiol could promote M1-like macrophage activation through cadherin-11 to aggravate the acute inflammation of TMJs.
The host immune response to bone biomaterials is vital in determining the fate of scaffolds and also the outcomes of bone regeneration. Mineralized collagen is an ideal tissue-engineering scaffold ...for bone repair; however, little is known about its immunomodulatory properties after implantation. In this study, extrafibrillarly-mineralized collagen (EMC) and intrafibrillarly-mineralized collagen (IMC) scaffolds with different nanostructures were fabricated and their immunomodulatory properties via macrophage polarization during bone regeneration were investigated. Micro-CT findings showed that the IMC scaffold yielded more new bone formation than the EMC scaffold. In the defect area, more CD68 + CD163 + M2-like macrophages were observed in the IMC group, while M1-like macrophages positive for CD68 and inducible nitric oxide synthase (iNOS) increased dramatically in the EMC group. We further demonstrated, from the protein and RNA levels, that M2-associated anti-inflammatory cytokines interleukin (IL)-10 and arginase-1 were highly expressed in the macrophages seeded on the IMC scaffold, while those seeded on the EMC scaffold expressed more M1-related genes iNOS and IL-6. Moreover, the macrophage polarization in response to the nanostructure of mineralized collagen scaffolds influenced the osteogenesis of human bone marrow stromal cells. These findings suggest that the nanostructure of mineralized collagen scaffolds affects macrophage functional polarization during bone regeneration. The immunomodulatory properties of biomaterial scaffolds can be a dictator of bone regeneration outcomes.
Tricellular adherens junctions are points of high tension that are central to the rearrangement of epithelial cells. However, the molecular composition of these junctions is unknown, making it ...difficult to assess their role in morphogenesis. Here, we show that Sidekick, an immunoglobulin family cell adhesion protein, is highly enriched at tricellular adherens junctions in Drosophila. This localization is modulated by tension, and Sidekick is itself necessary to maintain normal levels of cell bond tension. Loss of Sidekick causes defects in cell and junctional rearrangements in actively remodeling epithelial tissues like the retina and tracheal system. The adaptor proteins Polychaetoid and Canoe are enriched at tricellular adherens junctions in a Sidekick-dependent manner; Sidekick functionally interacts with both proteins and directly binds to Polychaetoid. We suggest that Polychaetoid and Canoe link Sidekick to the actin cytoskeleton to enable tricellular adherens junctions to maintain or transmit cell bond tension during epithelial cell rearrangements.
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•Sidekick is the hub of a complex specific to tricellular adherens junctions•Sidekick can sense and modulate cell bond tension•Sidekick is necessary for normal cell and junctional rearrangements•Sidekick links actin filaments to vertices through Canoe and Polychaetoid
Letizia et al. characterize the nature and function of tricellular adherens junctions. The transmembrane protein Sidekick is highly enriched at these junctions and connects to the actin cytoskeleton through Canoe and Polychaetoid. This complex can sense and modulate tension to promote normal cell rearrangements during developmental remodeling.
Mammalian members of the ErbB family, including the epidermal growth factor receptor (EGFR), can regulate transcription, DNA replication and repair through nuclear entry of either the full-length ...proteins or their cleaved cytoplasmic domains. In cancer cells, these nuclear functions contribute to tumor progression and drug resistance. Here, we examined whether the single
EGFR can also localize to the nucleus. A chimeric EGFR protein fused at its cytoplasmic C-terminus to DNA-binding and transcriptional activation domains strongly activated transcriptional reporters when overexpressed in cultured cells or
However, this activity was independent of cleavage and endocytosis. Without an exogenous activation domain, EGFR fused to a DNA-binding domain did not activate or repress transcription. Addition of the same DNA-binding and transcriptional activation domains to the endogenous
locus through genome editing led to no detectable reporter expression in wild-type or oncogenic contexts. These results show that, when expressed at physiological levels, the cytoplasmic domain of the
EGFR does not have access to the nucleus. Therefore, nuclear EGFR functions are likely to have evolved after vertebrates and invertebrates diverged.
Objectives. The effectiveness of Internet interventions for employees with depressive disorder remains controversial. We summarized all available evidence exploring the role of Internet interventions ...in reducing employees' depressive symptoms. Methods. This study was a comprehensive systematic review and meta-analysis that included acceptability and preliminary feasibility studies. We excluded programme descriptions, discussion articles and study protocols. We followed the PRISMA guidelines and searched MEDLINE, EMBASE, PsycINFO, the Cochrane Library and Web of Science from database inception to May 2021 for articles published in English. We extracted data concerning demographics, intervention format, including Internet interventions, control group conditions and outcome measures. We used a random-effects model and calculated Hedges' g values for the scores of employees receiving Internet interventions versus control conditions. This systematic review is registered as INPLASY202160082. Results. Data from 19 studies were included. These 19 studies included 5898 participants (2813 participants received Internet interventions, 3085 participants were in control groups). Conclusions. The findings suggest that Internet interventions can be effective in improving depression in employees. However, more randomized controlled trials are needed to provide better evidence regarding Internet interventions for employees with depression, and robust studies are needed to observe the effectiveness of Internet interventions.
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