Mechanical regulation of bone formation and resorption around implants in a mouse model of osteopenic bone.
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ABSTRACT:
SUBMITTER: Li Z
PROVIDER: S-EPMC6451400 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
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Project description:ObjectivesOur objective was to test the hypothesis that local delivery of a WNT protein therapeutic would support osseointegration of an unstable implant placed into an oversized osteotomy and subjected to functional loading.Materials and methodsUsing a split-mouth design in an ovariectomized (OVX) rat model, 50 titanium implants were placed in oversized osteotomies. Implants were subjected to functional loading. One-half of the implants were treated with a liposomal formulation of WNT3A protein (L-WNT3A); the other half received an identical liposomal formulation containing phosphate-buffered saline (PBS). Finite element modeling estimated peri-implant strains caused by functional loading. Histological, molecular, cellular, and quantitative micro-computed tomographic (µCT) imaging analyses were performed on samples from post-implant days (PID) 3, 7, and 14. Lateral implant stability was quantified at PID 7 and 14.ResultsFinite element analyses predicted levels of peri-implant strains incompatible with new bone formation. Micro-CT imaging, histological, and quantitative immunohistochemical (IHC) analyses confirmed that PBS-treated implants underwent fibrous encapsulation. In those cases where the peri-implant environment was treated with L-WNT3A, µCT imaging, histological, and quantitative IHC analyses demonstrated a significant increase in expression of proliferative (PCNA) and osteogenic (Runx2, Osterix) markers. One week after L-WNT3A treatment, new bone formation was evident, and two weeks later, L-WNT3A-treated gaps had a stiffer interface compared to PBS-treated gaps.ConclusionIn a rat model, unstable implants undergo fibrous encapsulation. If the same unstable implants are treated with L-WNT3A at the time of placement, then it results in significantly more peri-implant bone and greater interfacial stiffness.
| S-EPMC7722236 | biostudies-literature
Project description:BackgroundOsteoporosis is a significant barrier to the use of dental implants in the elderly for the treatment of tooth defects. Adipose derived stem cells (ADSCs) have demonstrated extensive potential for tissue repair and regeneration. The present study aimed to investigate the effectiveness of ADSCs engineered to express high levels of osteoprotegerin (OPG) for the treatment of bone loss in implant dentistry caused by estrogen deficiency.MethodsA rat model of osteoporosis was established through double oophorectomy, and the rats were treated by gene modified cells Adv-OPG-ADSCs. The effects of the treatment on maxilla tissue changes were evaluated using HE staining and micro-CT. Additionally, ALP and TRAP staining were used to assess osteoblast and osteoclast alterations. Finally, the changes in related osteoblast and osteoclast indicators were measured by RT-qPCR, Western blot, and ELISA.ResultsThe successfully generated high-OPG-expressing ADSCs led to increase of cell viability, proliferation, and osteoblast differentiation. Treatment with Adv-OPG-ADSCs significantly ameliorated maxillary morphology, trabecular volume reduction, and bone mineral density decline in the model of estrogen-deficient maxillary implant dentistry. Furthermore, the treatment was beneficial to promoting the generation of osteoblasts and inhibiting the generation of osteoclast. Adv-OPG-ADSCs increased OPG, ALP, OCN, and Runx-2 expressions in the maxilla while suppressing RANKL expression, and also increased the concentration of COL I and PINP, as well as decreased the concentration of CTX-1.ConclusionAdv-OPG-ADSCs promote the formation of osteoblasts and inhibit the generation of osteoclasts, thereby inhibiting bone absorption, facilitating bone formation, and promoting the repair of maxillary bone after dental implantation in the presence of osteoporosis-related complications, especially in the setting of estrogen deficiency, providing scientific basis for the application of Adv-OPG-ADSCs in the treatment of implant related osteoporosis.
| S-EPMC10560787 | biostudies-literature
Project description:The time-course of cancellous bone regeneration surrounding mechanically loaded implants affects implant fixation, and is relevant to determining optimal rehabilitation protocols following orthopaedic surgeries. We investigated the influence of controlled mechanical loading of titanium-coated polyether-ether ketone (PEEK) implants on osseointegration using time-lapsed, non-invasive, in vivo micro-computed tomography (micro-CT) scans. Implants were inserted into proximal tibial metaphyses of both limbs of eight female Sprague-Dawley rats. External cyclic loading (60 or 100 μm displacement, 1 Hz, 60 s) was applied every other day for 14 days to one implant in each rat, while implants in contralateral limbs served as the unloaded controls. Hind limbs were imaged with high-resolution micro-CT (12.5 μm voxel size) at 2, 5, 9, and 12 days post-surgery. Trabecular changes over time were detected by 3D image registration allowing for measurements of bone-formation rate (BFR) and bone-resorption rate (BRR). At day 9, mean %BV/TV for loaded and unloaded limbs were 35.5 ± 10.0% and 37.2 ± 10.0%, respectively, and demonstrated significant increases in bone volume compared to day 2. BRR increased significantly after day 9. No significant differences between bone volumes, BFR, and BRR were detected due to implant loading. Although not reaching significance (p = 0.16), an average 119% increase in pull-out strength was measured in the loaded implants. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:997-1006, 2017.
| S-EPMC5800527 | biostudies-literature
Project description:The utilization of biodegradable magnesium (Mg)-based implants for restoration of bone function following trauma represents a transformative approach in orthopaedic application. One such alloy, magnesium-10 weight percent gadolinium (Mg-10Gd), has been specifically developed to address the rapid degradation of Mg while enhancing its mechanical properties to promote bone healing. Previous studies have demonstrated that Mg-10Gd exhibits favorable osseointegration; however, it exhibits distinct ultrastructural adaptation in comparison to conventional implants like titanium (Ti). A crucial aspect that remains unexplored is the impact of Mg-10Gd degradation on the bone microarchitecture. To address this, we employed hierarchical three-dimensional imaging using synchrotron radiation in conjunction with image-based finite element modelling. By using the methods outlined, the vascular porosity, lacunar porosity and the lacunar-canaliculi network (LCN) morphology of bone around Mg-10Gd in comparison to Ti in a rat model from 4 weeks to 20 weeks post-implantation was investigated. Our investigation revealed that within our observation period, the degradation of Mg-10Gd implants was associated with significantly lower (p < 0.05) lacunar density in the surrounding bone, compared to Ti. Remarkably, the LCN morphology and the fluid flow analysis did not significantly differ for both implant types. In summary, a more pronounced lower lacunae distribution rather than their morphological changes was detected in the surrounding bone upon the degradation of Mg-10Gd implants. This implies potential disparities in bone remodelling rates when compared to Ti implants. Our findings shed light on the intricate relationship between Mg-10Gd degradation and bone microarchitecture, contributing to a deeper understanding of the implications for successful osseointegration. Graphical abstract Image 1 Highlights • Impact of Mg-10Gd implants on vascular porosity and LCN is assessed in comparison to standard Ti implants for the first time.• Multiscale imaging and image-based fluid flow simulation were utilized to study the vascular porosity and LCN.• Significantly lower lacunar distribution was observed in bone around Mg-10Gd compared to Ti implants.
| S-EPMC10412723 | biostudies-literature
Project description:DNA damage response plays a critical role in tumor growth, but little is known about its potential role in bone metabolism. We employed selective inhibitors of Chk1 and examined their effects on the proliferation and migration of mammary tumor cells as well as the development of osteoblasts and osteoclasts. Further, using a mouse model of bone metastasis we evaluated the effects of Chk1 inhibitors on bone quality. Chk1 inhibitors blocked the proliferation, survival, and migration of tumor cells in vitro and suppressed the development of bone-resorbing osteoclasts by downregulating NFATc1. In the mouse model, Chk1 inhibitor reduced osteolytic lesions and prevented mechanical weakening of the femur and tibia. Analysis of RNA-seq expression data indicated that the observed effects were mediated through the regulation of eukaryotic translation initiation factor 2 alpha, stress to the endoplasmic reticulum, S100 proteins, and bone remodeling-linked genes. Our findings suggest that targeting Chk1 signaling without adding DNA damaging agents may protect bone from degradation while suppressing tumor growth and migration.
| S-EPMC5823640 | biostudies-literature
Project description:The peroxisome proliferator-activated receptor gamma (PPAR?) regulates osteoblast and osteoclast differentiation, and is the molecular target of thiazolidinediones (TZDs), insulin sensitizers that enhance glucose utilization and adipocyte differentiation. However, clinical use of TZDs has been limited by side effects including a higher risk of fractures and bone loss. Here we demonstrate that the same post-translational modifications at S112 and S273, which influence PPAR? pro-adipocytic and insulin sensitizing activities, also determine PPAR? osteoblastic (pS112) and osteoclastic (pS273) activities. Treatment of either hyperglycemic or normoglycemic animals with SR10171, an inverse agonist that blocks pS273 but not pS112, increased trabecular and cortical bone while normalizing metabolic parameters. Additionally, SR10171 treatment modulated osteocyte, osteoblast, and osteoclast activities, and decreased marrow adiposity. These data demonstrate that regulation of bone mass and energy metabolism shares similar mechanisms suggesting that one pharmacologic agent could be developed to treat both diabetes and metabolic bone disease.
| S-EPMC5006645 | biostudies-literature
Project description:Docosahexaenoic acid (DHA) is an omega-3 fatty acid that exerts physiological effects via G protein-coupled receptor 120 (GPR120). In our previous studies, we figured out the inhibitory effects of DHA on TNF-α (Tumor necrosis factor-α)-induced osteoclastogenesis via GPR120 in vivo. Moreover, DHA directly suppressed RANKL expression in osteoblasts via GPR120 in vitro. In this study, we generated bone marrow chimeric mice using GPR120 deficient mice (GPR120-KO) to study the inhibitory effects of DHA on bone resorption and osteoclast formation. Bone marrow cells of wild-type (WT) or GPR120-KO mice were transplanted into irradiated recipient mice, which were WT or GPR120 deficient mice. The resulting chimeric mice contained stromal cells from the recipient and bone marrow cells, including osteoclast precursors, from the donor. These chimeric mice were used to perform a series of histological and microfocus computed tomography (micro-CT) analyses after TNF-α injection for induction of osteoclast formation with or without DHA. Osteoclast number and bone resorption were found to be significantly increased in chimeric mice, which did not express GPR120 in stromal cells, compared to chimeric mice, which expressed GPR120 in stromal cells. DHA was also found to suppress specific signaling pathways. We summarized that DHA suppressed TNF-α-induced stromal-dependent osteoclast formation and bone resorption via GPR120.
| S-EPMC10707107 | biostudies-literature
Project description:Coupling is the process that links bone resorption to bone formation in a temporally and spatially coordinated manner within the remodeling cycle. Several lines of evidence point to the critical roles of osteoclast-derived coupling factors in the regulation of osteoblast performance. Here, we used a fractionated secretomic approach and identified the axon-guidance molecule SLIT3 as a clastokine that stimulated osteoblast migration and proliferation by activating ?-catenin. SLIT3 also inhibited bone resorption by suppressing osteoclast differentiation in an autocrine manner. Mice deficient in Slit3 or its receptor, Robo1, exhibited osteopenic phenotypes due to a decrease in bone formation and increase in bone resorption. Mice lacking Slit3 specifically in osteoclasts had low bone mass, whereas mice with either neuron-specific Slit3 deletion or osteoblast-specific Slit3 deletion had normal bone mass, thereby indicating the importance of SLIT3 as a local determinant of bone metabolism. In postmenopausal women, higher circulating SLIT3 levels were associated with increased bone mass. Notably, injection of a truncated recombinant SLIT3 markedly rescued bone loss after an ovariectomy. Thus, these results indicate that SLIT3 plays an osteoprotective role by synchronously stimulating bone formation and inhibiting bone resorption, making it a potential therapeutic target for metabolic bone diseases.
| S-EPMC5873876 | biostudies-literature
Project description:BackgroundOsteomyelitis (OM) is an inflammatory condition of bone characterized by cortical bone devascularization and necrosis. Dysregulation of bone remodelling is triggered by OM. Bone remodelling is precisely coordinated by bone resorption and formation via a reversal phase. However, the cellular and molecular mechanisms underlying bone remodelling failure after osteomyelitis remain elusive.MethodsTo elucidate the cellular and molecular mechanism underlying bone healing after osteomyelitis, we employed single-cell RNA sequencing (scRNA-seq) to depict the atlas of human cortical bone in normal, infected and reconstructed states. Dimensionality reduction by t-stochastic neighbourhood embedding (t-SNE) and graph-based clustering were applied to analyse the detailed clusters of osteoclast lineages. After trajectory analysis of osteoclast lineages over pseudotime, real-time PCR and immunofluorescence (IF) staining were applied to identify marker gene expression of various osteoclast lineages in the osteoclast induction model and human bone sections, respectively. The potential function and communication of osteoclasts were analysed via gene set enrichment analysis (GSEA) and CellChat. The chemotactic ability of mesenchymal stem cells (MSCs) and osteoclast lineage cells in various differentiation states was determined by transwell assays and coculture assays. The effects of various osteoclast lineages on the osteogenic differentiation potential of MSCs were also determined by using this coculture system. A normal mouse tibia fracture model and an osteomyelitis-related tibia fracture model were generated via injection of luciferase-labelled Staphylococcus aureus to verify the relationships between a novel osteoclast lineage and MSCs. Then, the infection was detected by a bioluminescence imaging system. Finally, immunofluorescence staining was used to detect the expression of markers of MSCs and novel osteoclast lineages in different remodelling phases in normal and infected bone remodelling models.ResultsIn this study, we constructed a cell atlas encompassing normal, infected, and reconstructed cortical bone. Then, we identified a novel subset at the earlier stage of the osteoclast lineage that exhibited increased expression of IDO1, CCL3, and CCL4. These IDO1highCCL3highCCL4high cells, termed osteostaticytes (OSCs), were further regarded as the reservoir of osteoclasts in the reversal phase. Notably, OSCs exhibited the highest chemotactic activity, surpassing other lineage subsets. We also discovered that cells at the earlier stage of the osteoclast lineage play a significant role in recruiting mesenchymal stem cells (MSCs). Finally, the data revealed that OSCs might be positively related to the occurrence of bone MSCs and the contribution of bone remodelling.ConclusionCollectively, our findings revealed a novel stage (OSC) within the osteoclast lineage, potentially representing elusive bone reversal cells due to its increased chemotactic ability towards MSCs and potential contribution to bone remodelling. This study provides valuable insights into the intricate mechanisms of the reversal phase during bone remodelling and unveils potential therapeutic strategies for diseases associated with bone uncoupling.Translational potential of this articleThis study identified a new subset, referred to as IDO1(plus symbol) CCL3(plus symbol) CCL4(plus symbol) osteostaticytes which displayed the highest chemotactic activity among all osteoclast lineages and may serve as reversal cells in bone remodelling. These findings offer new insights and insights for understanding bone reversal-related diseases and may serve as novel therapeutic targets for conditions such as osteomyelitis and delayed bone healing.
| S-EPMC11254843 | biostudies-literature
Project description:The aim of this study was to compare osseointegration and surface characteristics of zirconia implants made by the powder injection molding (PIM) technique against those made by the conventional milling procedure in rabbit tibiae. Surface characteristics of 2 types of implants were evaluated. Sixteen rabbits received 2 types of external hex implants with similar geometry, either machined zirconia implants or PIM zirconia implants, in the tibiae. Removal torque tests and histomorphometric analyses were performed. The roughness of the PIM zirconia implants was higher than that of machined zirconia implants. The PIM zirconia implants exhibited significantly higher bone-implant contact and removal torque values than the machined zirconia implants (p<0.001). The osseointegration of the PIM zirconia implant is promising, and PIM, using the roughened mold etching technique, can produce substantially rougher surfaces on zirconia implants.
| S-EPMC5559725 | biostudies-other