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Gastrointestinal enterochromaffin cells regulate bone and gut homeostasis via serotonin (5-hydroxytryptamine [5-HT]) production. A recent report suggested that gut microbes regulate 5-HT levels; however, the precise underlying molecular mechanisms are unexplored. Here, we reveal that the cation channel Piezo1 in the gut acts as a sensor of single-stranded RNA (ssRNA) governing 5-HT production. Intestinal epithelium-specific deletion of mouse Piezo1 profoundly disturbed gut peristalsis, impeded experimental colitis, and suppressed serum 5-HT levels. Because of systemic 5-HT deficiency, conditional knockout of Piezo1 increased bone formation. Notably, fecal ssRNA was identified as a natural Piezo1 ligand, and ssRNA-stimulated 5-HT synthesis from the gut was evoked in a MyD88/TRIF-independent manner. Colonic infusion of RNase A suppressed gut motility and increased bone mass. These findings suggest gut ssRNA as a master determinant of systemic 5-HT levels, indicating the ssRNA-Piezo1 axis as a potential prophylactic target for treatment of bone and gut disorders.
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Osso e Ossos/metabolismo , Colo/metabolismo , Motilidade Gastrointestinal/genética , Canais Iônicos/metabolismo , RNA/metabolismo , Serotonina/biossíntese , Serotonina/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Osso e Ossos/citologia , Cálcio/metabolismo , Colite/genética , Colite/metabolismo , Colite/prevenção & controle , Colo/fisiologia , Fezes/química , Feminino , Motilidade Gastrointestinal/fisiologia , Células HEK293 , Humanos , Imuno-Histoquímica , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Canais Iônicos/genética , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microbiota/efeitos dos fármacos , Fator 88 de Diferenciação Mieloide/metabolismo , Osteoclastos/metabolismo , Pirazinas/farmacologia , RNA/farmacologia , Ribonuclease Pancreático/administração & dosagem , Serotonina/sangue , Serotonina/deficiência , Tiadiazóis/farmacologiaRESUMO
Nutritional supplementation with probiotics can prevent pathologic bone loss. Here we examined the impact of supplementation with Lactobacillus rhamnosus GG (LGG) on bone homeostasis in eugonadic young mice. Micro-computed tomography revealed that LGG increased trabecular bone volume in mice, which was due to increased bone formation. Butyrate produced in the gut following LGG ingestion, or butyrate fed directly to germ-free mice, induced the expansion of intestinal and bone marrow (BM) regulatory T (Treg) cells. Interaction of BM CD8+ T cells with Treg cells resulted in increased secretion of Wnt10b, a bone anabolic Wnt ligand. Mechanistically, Treg cells promoted the assembly of a NFAT1-SMAD3 transcription complex in CD8+ cells, which drove expression of Wnt10b. Reducing Treg cell numbers, or reconstitution of TCRß-/- mice with CD8+ T cells from Wnt10b-/- mice, prevented butyrate-induced bone formation and bone mass acquisition. Thus, butyrate concentrations regulate bone anabolism via Treg cell-mediated regulation of CD8+ T cell Wnt10b production.
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Butiratos/farmacologia , Osteogênese/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Proteínas Wnt/metabolismo , Animais , Butiratos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Comunicação Celular , Proliferação de Células/efeitos dos fármacos , Feminino , Lacticaseibacillus rhamnosus/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Probióticos/administração & dosagem , Probióticos/metabolismo , Linfócitos T Reguladores/citologia , Proteínas Wnt/genéticaRESUMO
The silent information regulator T1 (SIRT1) is linked to longevity and is a crucial mediator of osteoblast function. We investigated the direct role of Sirt1 during bone modeling and remodeling stages in vivo using Tamoxifen-inducible osteoblast-specific Sirt1 conditional knockout (cKO) mice. cKO mice exhibited lower trabecular and cortical bone mass in the distal femur. These phenotypes were coupled with lower bone formation and bone resorption. Metabolomics analysis revealed that the metabolites involved in glycolysis were significantly decreased in cKO mice. Further analysis of the quantitative acetylome revealed 11 proteins with upregulated acetylation levels in both the femur and calvaria of cKO mice. Cross-analysis identified four proteins with the same upregulated lysine acetylation site in both the femur and calvaria of cKO mice. A combined analysis of the metabolome and acetylome, as well as immunoprecipitation, gene knockout, and site-mutation experiments, revealed that Sirt1 deletion inhibited glycolysis by directly binding to and increasing the acetylation level of Glutamine oxaloacetic transaminase 1 (GOT1). In conclusion, our study suggested that Sirt1 played a crucial role in regulating osteoblast metabolism to maintain bone homeostasis through its deacetylase activity on GOT1. These findings provided a novel insight into the potential targeting of osteoblast metabolism for the treatment of bone-related diseases.
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Glicólise , Homeostase , Camundongos Knockout , Osteoblastos , Sirtuína 1 , Animais , Camundongos , Acetilação , Osso e Ossos/metabolismo , Fêmur/metabolismo , Osteoblastos/metabolismo , Osteogênese , Sirtuína 1/metabolismo , Sirtuína 1/genéticaRESUMO
Bone remodeling consists of resorption by osteoclasts (OCs) and formation by osteoblasts (OBs). Precise coordination of these activities is required for the resorbed bone to be replaced with an equal amount of new bone in order to maintain skeletal mass throughout the lifespan. This coordination of remodeling processes is referred to as the "coupling" of resorption to bone formation. In this review, we discuss the essential role for OCs in coupling resorption to bone formation, mechanisms for this coupling, and how coupling becomes less efficient or disrupted in conditions of bone loss. Lastly, we provide perspectives on targeting coupling to treat human bone disease.
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Reabsorção Óssea , Osteoclastos , Remodelação Óssea , Humanos , Osteoblastos , OsteogêneseRESUMO
The Hippo pathway plays an imperative role in cellular processes such as differentiation, regeneration, cell migration, organ growth, apoptosis, and cell cycle. Transcription coregulator component of Hippo pathway, YAP1, promotes transcription of genes involved in cell proliferation, migration, differentiation, and suppressing apoptosis. However, its role in epimorphic regeneration has not been fully explored. The axolotl is a well-established model organism for developmental biology and regeneration studies. By exploiting its remarkable regenerative capacity, we investigated the role of Yap1 in the early blastema stage of limb regeneration. Depleting Yap1 using gene-specific morpholinos attenuated the competence of axolotl limb regeneration evident in bone formation defects. To explore the affected downstream pathways from Yap1 down-regulation, the gene expression profile was examined by employing LC-MS/MS technology. Based on the generated data, we provided a new layer of evidence on the putative roles of increased protease inhibition and immune system activities and altered ECM composition in diminished bone formation capacity during axolotl limb regeneration upon Yap1 deficiency. We believe that new insights into the roles of the Hippo pathway in complex structure regeneration were granted in this study.
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Ambystoma mexicanum , Osteogênese , Animais , Ambystoma mexicanum/genética , Regulação para Baixo , Cromatografia Líquida , Transdução de Sinais , Espectrometria de Massas em Tandem , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
Hem1 (hematopoietic protein 1), a hematopoietic cell-specific member of the Hem family of cytoplasmic adaptor proteins, is essential for lymphopoiesis and innate immunity as well as for the transition of hematopoiesis from the fetal liver to the bone marrow. However, the role of Hem1 in bone cell differentiation and bone remodeling is unknown. Here, we show that deletion of Hem1 resulted in a markedly increase in bone mass because of defective bone resorption in mice of both sexes. Hem1-deficient osteoclast progenitors were able to differentiate into osteoclasts, but the osteoclasts exhibited impaired osteoclast fusion and decreased bone-resorption activity, potentially because of decreased mitogen-activated protein kinase and tyrosine kinase c-Abl activity. Transplantation of bone marrow hematopoietic stem and progenitor cells from wildtype into Hem1 knockout mice increased bone resorption and normalized bone mass. These findings indicate that Hem1 plays a pivotal role in the maintenance of normal bone mass.
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Proteínas Adaptadoras de Transdução de Sinal , Reabsorção Óssea , Osteoclastos , Animais , Feminino , Masculino , Camundongos , Reabsorção Óssea/genética , Reabsorção Óssea/metabolismo , Diferenciação Celular , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Camundongos Knockout , Osteoclastos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
Parathyroid hormone (PTH) serves dual roles in bone metabolism, exhibiting both anabolic and catabolic effects. The anabolic properties of PTH have been utilized in the treatment of osteoporosis with proven efficacy in preventing fractures. Despite these benefits, PTH can be administered therapeutically for up to 2 years, and its use in patients with underlying malignancies remains a subject of ongoing debate. These considerations underscore the need for a more comprehensive understanding of the underlying mechanisms. p21-activated kinase 4 (PAK4) is involved in bone resorption and cancer-associated osteolysis; however, its role in osteoblast function and PTH action remains unknown. Therefore, in this study, we aimed to clarify the role of PAK4 in osteoblast function and its effects on PTH-induced anabolic activity. PAK4 enhanced MC3T3-E1 osteoblast viability and proliferation and upregulated cyclin D1 expression. PAK4 also augmented osteoblast differentiation, as indicated by increased mineralization found by alkaline phosphatase and Alizarin Red staining. Treatment with PTH (1-34), an active PTH fragment, stimulated PAK4 expression and phosphorylation in a protein kinase A-dependent manner. In addition, bone morphogenetic protein-2 (which is known to promote bone formation) increased phosphorylated PAK4 (p-PAK4) and PAK4 levels. PAK4 regulated the expression of both phosphorylated and total ß-catenin, which are critical for osteoblast proliferation and differentiation. Moreover, p-PAK4 directly interacted with ß-catenin, and disruption of ß-catenin's binding to T-cell factor impaired PAK4- and PTH-induced osteoblast differentiation. Our findings elucidate the effect of PAK4 on enhancing bone formation in osteoblasts and its pivotal role in the anabolic activity of PTH mediated through its interaction with ß-catenin. These insights improve the understanding of the mechanisms underlying PTH activity and should inform the development of more effective and safer osteoporosis treatments.
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Diferenciação Celular , Proliferação de Células , Osteoblastos , Hormônio Paratireóideo , beta Catenina , Quinases Ativadas por p21 , Animais , Humanos , Camundongos , beta Catenina/metabolismo , beta Catenina/genética , Calcificação Fisiológica/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina D1/metabolismo , Ciclina D1/genética , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Quinases Ativadas por p21/metabolismo , Quinases Ativadas por p21/genética , Hormônio Paratireóideo/farmacologia , Hormônio Paratireóideo/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células CultivadasRESUMO
OBJECTIVE: To investigate the effect of intermittent parathyroid hormone (iPTH) administration on pathological new bone formation during treatment of ankylosing spondylitis-related osteoporosis. METHODS: Animal models with pathological bone formation caused by hypothetical AS pathogenesis received treatment with iPTH. We determined the effects of iPTH on bone loss and the formation of pathological new bone with micro-computed tomography (micro-CT) and histological examination. In addition, the tamoxifen-inducible conditional knockout mice (CAGGCre-ERTM; PTHflox/flox, PTH-/-) was established to delete PTH and investigate the effect of endogenous PTH on pathological new bone formation. RESULTS: iPTH treatment significantly improved trabecular bone mass in the modified collagen-induced arthritis (m-CIA) model and unbalanced mechanical loading models. Meanwhile, iPTH treatment did not enhance pathological new bone formation in all types of animal models. Endogenous PTH deficiency had no effects on pathological new bone formation in unbalanced mechanical loading models. CONCLUSION: Experimental animal models of AS treated with iPTH show improvement in trabecular bone density, but not entheseal pathological bone formationï¼indicating it may be a potential treatment for inflammatory bone loss does in AS.
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Osteogênese , Hormônio Paratireóideo , Animais , Hormônio Paratireóideo/administração & dosagem , Hormônio Paratireóideo/farmacologia , Hormônio Paratireóideo/uso terapêutico , Osteogênese/efeitos dos fármacos , Camundongos , Osteoporose/tratamento farmacológico , Osteoporose/patologia , Camundongos Knockout , Masculino , Microtomografia por Raio-X , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/patologia , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Densidade Óssea/efeitos dos fármacosRESUMO
Midfacial morphology varies between hominoids, in particular between great apes and humans for which the face is small and retracted. The underlying developmental processes for these morphological differences are still largely unknown. Here, we investigate the cellular mechanism of maxillary development (bone modelling, BM), and how potential changes in this process may have shaped facial evolution. We analysed cross-sectional developmental series of gibbons, orangutans, gorillas, chimpanzees and present-day humans (n = 183). Individuals were organized into five age groups according to their dental development. To visualize each species's BM pattern and corresponding morphology during ontogeny, maps based on microscopic data were mapped onto species-specific age group average shapes obtained using geometric morphometrics. The amount of bone resorption was quantified and compared between species. Great apes share a highly similar BM pattern, whereas gibbons have a distinctive resorption pattern. This suggests a change in cellular activity on the hominid branch. Humans possess most of the great ape pattern, but bone resorption is high in the canine area from birth on, suggesting a key role of canine reduction in facial evolution. We also observed that humans have high levels of bone resorption during childhood, a feature not shared with other apes.
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Reabsorção Óssea , Hominidae , Animais , Humanos , Hominidae/anatomia & histologia , Hylobates , Estudos Transversais , Gorilla gorilla , Pan troglodytes , Morfogênese , Evolução BiológicaRESUMO
Vascular dysfunction contributes to the development of osteopenia in hypertensive patients, as decreased blood supply to bones results in tissue damage and dysfunction. The effect of anti-hypertensive medicines on bone mass in hypertensive individuals is inconclusive because of the varied mechanism of their action, and suggests that reducing blood pressure (BP) alone is insufficient to enhance bone mass in hypertension. Pentoxifylline (PTX), a hemorheological drug, improves blood flow by reducing blood viscosity and angiogenesis, also has an osteogenic effect. We hypothesized that improving vascular function is critical to increasing bone mass in hypertension. To test this, we screened various anti-hypertensive drugs for their in vitro osteogenic effect, from which timolol and hydralazine were selected. In adult female spontaneously hypertensive rats (SHRs), timolol and hydralazine did not improve vascular function and bone mass, but PTX improved both. In female SHR animals, PTX restored bone mass, strength and mineralization, up to the level of normotensive control rats. In addition, we observed lower blood vasculature in the femur of adult SHR animals, and PTX restored them. PTX also restored the bone vascular and angiogenesis parameters that had been impaired in OVX SHR compared to sham SHR. This study demonstrates the importance of vascular function in addition to increased bone mass for improving bone health as achieved by PTX without affecting BP, and suggests a promising treatment option for osteoporosis in hypertensive patients, particularly at-risk postmenopausal women.
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Hipertensão , Pentoxifilina , Humanos , Ratos , Feminino , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Densidade Óssea , Timolol/farmacologia , Timolol/uso terapêutico , Hipertensão/tratamento farmacológico , Ratos Endogâmicos SHR , Pentoxifilina/farmacologia , Hidralazina/farmacologia , Hidralazina/uso terapêutico , Pressão SanguíneaRESUMO
A new target that stimulates bone formation is needed to overcome limitations of current anti-osteoporotic drugs. Myokines, factors secreted from muscles, may modulate it. In this study, we investigated the role of aortic carboxypeptidase-like protein (ACLP), which is highly expressed in skeletal muscles, on bone formation. MC3T3-E1 cells and/or calvaria osteoblasts were treated with recombinant N-terminal mouse ACLP containing a signal peptide [rmACLP (N)]. The expression and secretion of ACLP were higher in skeletal muscle and differentiated myotube than in other tissues and undifferentiated myoblasts, respectively. rmACLP (N) increased bone formation, ALP activity, and phosphorylated p38 mitogen-activated protein (MAP) kinase in osteoblasts; reversal was achieved by pre-treatment with a TGF-ß receptor inhibitor. Under H2 O2 treatment, rmACLP (N) increased osteoblast survival, phosphorylated p38 MAP kinase, and the nuclear translocation of FoxO3a in osteoblasts. H2 O2 treatment caused rmACLP (N) to suppress its apoptotic, oxidative, and caspase-9 activities. rmACLP (N)-stimulated osteoblast survival was reversed by pre-treatment with a p38 inhibitor, a TGF-ß-receptor II blocking antibody, and a FoxO3a shRNA. Conditioned media (CM) from muscle cells stimulated osteoblast survival under H2 O2 treatment, in contrast to CM from ACLP knockdown muscle cells. rmACLP (N) increased the expressions of FoxO3a target anti-oxidant genes such as Sod2, Trx2, and Prx5. In conclusion, ACLP stimulated the differentiation and survival of osteoblasts. This led to the stimulation of bone formation by the activation of p38 MAP kinase and/or FoxO3a via TGF-ß receptors. These findings suggest a novel role for ACLP in bone metabolism as a putative myokine.
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Carboxipeptidases , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Camundongos , Diferenciação Celular/fisiologia , Carboxipeptidases/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Osteogênese , Osteoblastos/metabolismo , FosforilaçãoRESUMO
INTRODUCTION: The formation of normal bone and bone healing requires the cAMP-responsive element binding protein 3-like-1 (Creb3l1) transmembrane transcription factor, as deletion of the murine CREB3L1 results in osteopenic animals with limited capacity to repair bone after a fracture. Creb3l1 undergoes regulated intramembrane proteolysis (RIP) to release the N-terminal transcription activating (TA) fragment that enters the nucleus and regulates the expression of target genes. METHODS: To expand our understanding of Creb3l1's role in skeletal development and skeletal patterning, we aimed to generate animals expressing only the TA fragment of Creb3l1 lacking the transmembrane domain and thereby not regulated through RIP. However, the CRISPR/Cas9-mediated genome editing in zebrafish Danio rerio caused a frameshift mutation that added 56 random amino acids at the C-terminus of the TA fragment (TA+), making it unable to enter the nucleus. Thus, TA+ does not regulate transcription, and the creb3l1TA+/TA+ fish do not mediate creb3l1-dependent transcription. RESULTS: We document that the creb3l1TA+/TA+ fish exhibit defects in the patterning of caudal fin lepidotrichia, with significantly distalized points of proximal bifurcation and decreased secondary bifurcations. Moreover, using the caudal fin amputation model, we show that creb3l1TA+/TA+ fish have decreased regeneration and that their regenerates replicate the distalization and bifurcation defects observed in intact fins of creb3l1TA+/TA+ animals. These defects correlate with altered expression of the shha and ptch2 components of the Sonic Hedgehog signaling pathway in creb3l1TA+/TA+ regenerates. CONCLUSION: Together, our results uncover a previously unknown intersection between Creb3l1 and the Sonic Hedgehog pathway and document a novel role of Creb3l1 in tissue patterning.
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Positive regulators of bone formation, such as mechanical loading and PTH, stimulate and negative regulators, such as aging and glucocorticoid excess, suppress IL-11 gene transcription in osteoblastic cells. Signal transduction from mechanical loading and PTH stimulation involves two pathways: one is Ca2+-ERK-CREB pathway which facilitates binding of ∆FosB/JunD to the AP-1 site to enhance IL-11 gene transcription, and the other is Smad1/5 phosphorylation that promotes IL-11 gene transcription via SBE binding and complex formation with ∆FosB/JunD. The increased IL-11 suppresses Sost expression via IL-11Rα-STAT1/3-HDAC4/5 pathway and enhances Wnt signaling in the bone to stimulate bone formation. Thus, IL-11 mediates stimulatory and inhibitory signals of bone formation by affecting Wnt signaling. Physiologically important stimulation of bone formation is exercise-induced mechanical loading, but exercise simultaneously requires energy source for muscle contraction. Exercise-induced stimulation of IL-11 expression in the bone increases the secretion of IL-11 from the bone. The increased circulating IL-11 acts like a hormone to enhance adipolysis as an energy source with a reduction in adipogenic differentiation via a suppression of Dkk1/2 expression in the adipose tissue. Such bone-fat linkage can be a mechanism whereby exercise increases bone mass and, at the same time, maintains energy supply from the adipose tissue.
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PURPOSE OF REVIEW: Over the past two decades, significant progress has been made to untangle the etiology of inflammation and new bone formation (NBF) associated with axial spondyloarthritis (axSpA). However, exact mechanisms as to how the disease initiates and develops remain elusive. RECENT FINDINGS: Type 3 immunity, centered around the IL-23/IL-17 axis, has been recognized as a key player in the pathogenesis of axSpA. Multiple hypotheses associated with HLA-B*27 have been proposed to account for disease onset and progression of axSpA, potentially by driving downstream T cell responses. However, HLA-B*27 alone is not sufficient to fully explain the development of axSpA. Genome-wide association studies (GWAS) identified several genes that are potentially relevant to disease pathogenesis leading to a better understanding of the immune activation seen in axSpA. Furthermore, gut microbiome studies suggest an altered microbiome in axSpA, and animal studies suggest a pathogenic role for immune cells migrating from the gut to the joint. Recent studies focusing on the pathogenesis of new bone formation (NBF) have highlighted the importance of endochondral ossification, mechanical stress, pre-existing inflammation, and activated anabolic signaling pathways during the development of NBF. Despite the complex etiology of axSpA, recent studies have shed light on pivotal pieces that could lead to a better understanding of the pathogenic events in axSpA.
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Espondiloartrite Axial , Espondilartrite , Espondilite Anquilosante , Humanos , Espondilartrite/genética , Estudo de Associação Genômica Ampla , Espondilite Anquilosante/genética , Espondilite Anquilosante/complicações , Inflamação/genética , Inflamação/complicações , Antígenos HLA-B/genéticaRESUMO
AIMS: To histologically compare osseointegration and crestal bone healing between newly introduced tapered, self-cutting bone-level test implants and tapered bone-level control implants in sites with fully healed sites. METHODS: Sixty-six implants (33 test, 33 control) were placed 1 mm subcrestally in a minipig model and underwent qualitative histologic and quantitative histometric analyses after 3, 6 and 12 weeks of submerged healing. The primary and secondary outcomes were the bone-to-implant contact (BIC) and first bone-to-implant contact (fBIC). Outcomes between the test and control implants were statistically compared. RESULTS: The BIC values of the test implants were comparable and non-inferior over the time points studied, except for the 12 weeks time point which showed statistically significantly higher BIC values of the test (88.07 ± 5.35%) compared to the control implants (80.88 ± 7.51%) (p = .010). Similarly comparable and non-inferior were the fBIC values, except for the 6-week outcome, which showed statistically higher values for the test (-546.5 ± 450.80 µm) compared to the control implants (-75.7 ± 100.59 µm). fBIC results for the test implants were qualitatively more stable and consistent between test time points. CONCLUSION: Novel self-cutting bone-level test implants demonstrated superior osseointegration and similar bone levels compared to conventional bone-level implants after a healing period of 12 weeks in healed ridges.
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PURPOSE: To histometrically compare the osseointegration and crestal bone healing of a novel tapered, self-cutting tissue-level test implant with a standard tissue-level control implant in a submerged healing regimen. MATERIALS AND METHODS: In a mandibular minipig model, implants were inserted and evaluated histometrically after a healing period of 3, 6, and 12 weeks. The primary outcome was the evaluation of bone-to-implant contact (BIC) and secondary outcomes were primary stability as per insertion torque and first BIC (fBIC). Outcomes for the test and control implants were compared using Wilcoxon signed-rank tests and mixed linear regression models. RESULTS: Insertion torque values were significantly higher for the test (50.0 ± 26.4 Ncm) compared to the control implants (35.2 ± 19.7 Ncm, p = .0071). BIC values of test implants were non-inferior to those of control implants over the investigated study period. After 12 weeks, the corresponding values measured were 81.62 ± 11.12% and 90.41 ± 4.81% (p = .1763) for test and control implants, respectively. Similarly, no statistical difference was found for fBIC values, except for the 12 weeks outcome that showed statistically lower values for the test (-675.58 ± 590.88 µm) compared to control implants (-182.75 ± 197.40 µm, p = .0068). CONCLUSIONS: Novel self-cutting tissue-level implants demonstrated noninferior osseointegration and crestal bone height maintenance to the tissue-level implants. Histometric outcomes between both implants demonstrated test implants were statistically noninferior to control implants, despite substantial differences in the bone engagement mechanism and resulting differences in insertion torque and qualitative bone healing patterns.
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OBJECTIVES: Collagen membranes are extensively used for guided bone regeneration procedures, primarily for horizontal bone augmentation. More recently, it has been demonstrated that collagen membranes promote bone regeneration. Present study aimed at assessing if structural modifications of collagen membranes may enhance their osteoconductive capacity. METHODS: Twenty-four adult Wistar rats were used. Bilateral calvaria defects with a diameter of 5 mm were prepared and covered with prototypes of collagen membranes (P1 or P2). The P1 membrane (positive control) presented a lower onset temperature of protein denaturation and a higher solubility than the P2 membrane (test). The contralateral defects were left uncovered (NC). After 1 and 4 weeks, the animals were euthanized. A microcomputed tomography analysis of the harvested samples was performed within and above the bony defect. Undecalcified ground sections were subjected to light microscopy and morphometric analysis. RESULTS: Bone formation was observed starting from the circumferential borders of the defects in all groups at 1-week of healing. The foci of ossification were observed at the periosteal and dura mater sites, with signs of collagen membrane mineralization. However, there was no statistically significant difference between the groups. At 4 weeks, remnants of the collagen fibers were embedded in the newly formed bone. In the P2 group, significantly more bone volume, more new bone, and marrow spaces compared to the NC group were observed. Furthermore, the P2 group showed more bone volume ectocranially then the P1 group. CONCLUSIONS: Bone formation subjacent to a P2 membrane was superior than subjacent to the P1 membrane and significantly better compared to the control. Modifications of the physico-chemical properties may enhance the osteoconductive competence of collagen membranes, supporting bone formation outside the bony defects.
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OBJECTIVES: The aim of the present study was to compare a novel tapered, double-threaded self-tapping tissue-Level design implant (TLC) to a well-established parallel walled tissue-level (TL) implant in terms of primary and secondary stability over time. MATERIALS AND METHODS: Test TLC (n = 10/per timepoint) and control TL (n = 10/per timepoint) implants were placed in the mandible of minipigs and left for submerged healing for 3, 6, and 12 weeks. Maximum insertion torque and implant stability quotient (ISQ) were measured for each implant at placement. Osseointegration and cortical bone maintenance were histologically evaluated by measuring total bone-to-implant contact (BIC) and first bone-to-implant contact (fBIC). RESULTS: A significantly higher maximum insertion torque was measured for the test implant TLC compared to the control TL implant (57.83 ± 24.73 Ncm and 22.62 ± 23.16 Ncm, respectively; p < .001). The mean ISQ values were comparable between the two implant types (75.00 ± 6.70 for TL compared to 75.40 ± 3.20 for TLC, p = .988). BIC was comparable between both implant types at each of the evaluated time points. The fBIC was found to be significantly more coronal at 12 weeks for the TLC implant compared to the TL implant (0.31 ± 0.83 mm for TLC compared to -0.22 ± 0.85 for TL, p = .027). CONCLUSION: The novel tapered tissue level design implant showed improved primary stability and an overall improved crestal bone height maintenance compared to the parallel walled design at 12 weeks.
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BACKGROUND: The inclusion of a connecting path in a porous implant can promote nutrient diffusion to cells and enhance bone ingrowth. Consequently, this study aimed to evaluate the biomechanical, radiographic, and histopathological performance of a novel 3D-printed porous suture anchor in a rabbit femur model. METHODS: Three test groups were formed based on the type of suture anchor (SA): Commercial SA (CSA, Group A, n = 20), custom solid SA (CSSA, Group B, n = 20), and custom porous SA (CPSA, Group C, n = 20). The SAs were implanted in the lateral femoral condyle of the right leg in each rabbit. The rabbits (New Zealand white rabbits, male, mean body weight of 2.8 ± 0.5 kg, age 8 months) underwent identical treatment and were randomized into experimental and control groups via computer-generated randomization. Five rabbits (10 femoral condyles) were euthanized at 0, 4, 8, and 12 weeks post-implantation for micro-CT, histological analysis, and biomechanical testing. RESULTS: At 12 weeks, the CPSA showed a higher BV/TV (median 0.7301, IQR 0.7276-0.7315) than the CSSA and CSA. The histological analysis showed mineralized osteocytes near the SA. At 4 weeks, new bone was observed around the CPSA and had penetrated its porous structure. By 12 weeks, there was no significant difference in ultimate failure load between the CSA and CPSA. CONCLUSIONS: We demonstrated that the innovative 3D-printed porous suture anchor exhibited comparable pullout strength to conventional threaded suture anchors at the 12-week postoperative time-point period. Furthermore, our porous anchor design enhanced new bone formation and facilitated bone growth into the implant structure, resulting in improved biomechanical stability.
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Fêmur , Impressão Tridimensional , Âncoras de Sutura , Titânio , Animais , Coelhos , Fêmur/cirurgia , Fêmur/diagnóstico por imagem , Fêmur/patologia , Porosidade , Masculino , Fenômenos Biomecânicos , Microtomografia por Raio-XRESUMO
RNA-binding proteins (RBPs), which are key effectors of gene expression, play critical roles in inflammation and immune regulation. However, the potential biological function of RBPs in ankylosing spondylitis (AS) remains unclear. We identified differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) of five patients with AS and three healthy persons by RNA-seq, obtained differentially expressed RBPs by overlapping DEGs and RBPs summary table. RIOK3 was selected as a target RBP and knocked down in mouse bone marrow mesenchymal stem cells (mBMSCs), and transcriptomic studies of siRIOK3 mBMSCs were performed again using RNA-seq. Results showed that RIOK3 knockdown inhibited the expression of genes related to osteogenic differentiation, ribosome function, and ß-interferon pathways in mBMSCs. In vitro experiments have shown that RIOK3 knockdown reduced the osteogenic differentiation ability of mBMSCs. Collectively, RIOK3 may affect the differentiation of mBMSCs and participate in the pathogenesis of AS, especially pathological bone formation.