Force-induced Caspase-1-dependent pyroptosis regulates orthodontic tooth movement

Pyroptosis,an inflammatory caspase-dependent programmed cell death,plays a vital role in maintaining tissue homeostasis and activating inflammatory responses.Orthodontic tooth movement(OTM)is an aseptic force-induced inflammatory bone remodeling process mediated by the activation of periodontal ligament(PDL)progenitor cells.However,whether and how force induces PDL progenitor cell pyroptosis,thereby influencing OTM and alveolar bone remodeling remains unknown.In this study,we found that mechanical force induced the expression of pyroptosis-related markers in rat OTM and alveolar bone remodeling process.Blocking or enhancing pyroptosis level could suppress or promote OTM and alveolar bone remodeling respectively.Using Caspase-1^(−/−)mice,we further demonstrated that the functional role of the force-induced pyroptosis in PDL progenitor cells depended on Caspase-1.Moreover,mechanical force could also induce pyroptosis in human ex-vivo force-treated PDL progenitor cells and in compressive force-loaded PDL progenitor cells in vitro,which influenced osteoclastogenesis.Mechanistically,transient receptor potential subfamily V member 4 signaling was involved in force-induced Caspase-1-dependent pyroptosis in PDL progenitor cells.Overall,this study suggested a novel mechanism contributing to the modulation of osteoclastogenesis and alveolar bone remodeling under mechanical stimuli,indicating a promising approach to accelerate OTM by targeting Caspase-1.

Effect of the nano/microscale structure of biomaterial scaffolds on bone regeneration

Natural bone is a mineralized biological material, which serves a supportive and protective framework for the body, stores minerals for metabolism, and produces blood cells nourishing the body. Normally, bone has an innate capacity to heal from damage.However, massive bone defects due to traumatic injury, tumor resection, or congenital diseases pose a great challenge to reconstructive surgery. Scaffold-based tissue engineering(TE) is a promising strategy for bone regenerative medicine, because biomaterial scaffolds show advanced mechanical properties and a good degradation profile, as well as the feasibility of controlled release of growth and differentiation factors or immobilizing them on the material surface. Additionally, the defined structure of biomaterial scaffolds, as a kind of mechanical cue, can influence cell behaviors, modulate local microenvironment and control key features at the molecular and cellular levels. Recently, nano/micro-assisted regenerative medicine becomes a promising application of TE for the reconstruction of bone defects. For this reason, it is necessary for us to have in-depth knowledge of the development of novel nano/micro-based biomaterial scaffolds. Thus, we herein review the hierarchical structure of bone, and the potential application of nano/micro technologies to guide the design of novel biomaterial structures for bone repair and regeneration.

Macrophage-derived small extracellular vesicles promote biomimetic mineralized collagen-mediated endogenous bone regeneration

Macrophages play an important role in material-related immune responses and bone formation,but the functionality of macrophage-derived extracellular vesicles(EVs)in material-mediated bone regeneration is still unclear.Here,we evaluated intracellular communication through small extracellular vesicles(sEVs)and its effects on endogenous bone regeneration mediated by biomimetic intrafibrillarly mineralized collagen(IMC).After implantation in the bone defect area,IMC generated more neobone and recruited more mesenchymal stem cells(MSCs)than did extrafibrillarly mineralized collagen(EMC).More CD63+CD90+and CD63+CD163+cells were detected in the defect area in the IMC group than in the EMC group.To determine the functional roles of sEVs,extracellular vesicles from macrophages cultured on different mineralized collagen were isolated,and they showed no morphological differences.However,macrophage-derived sEVs in the IMC group showed an enhanced Young’s modulus and exerted beneficial effects on the osteogenic differentiation of bone marrow MSCs by increasing the expression of the osteoblastic differentiation markers BMP2,BGLAP,COL1,and OSX and calcium nodule formation.Mechanistically,sEVs from IMC-treated macrophages facilitated MSC osteogenesis through the BMP2/Smad5 pathway,and blocking sEV secretion with GW4869 significantly impaired MSC proliferative,immunomodulative and osteogenic potential.Taken together,these findings show that macrophage-derived sEVs may serve as an emerging functional tool in biomaterial-mediated endogenous bone regeneration.

Prim-O-glucosylcimifugin ameliorates aging-impaired endogenous tendon regeneration by rejuvenating senescent tendon stem/progenitor cells

Adult tendon stem/progenitor cells(TSPCs)are essential for tendon maintenance,regeneration,and repair,yet they become susceptible to senescence with age,impairing the self-healing capacity of tendons.In this study,we employ a recently developed deep-learning-based efficacy prediction system to screen potential stemness-promoting and senescence-inhibiting drugs from natural products using the transcriptional signatures of stemness.The top-ranked candidate,prim-O-glucosylcimifugin(POG),a saposhnikovia root extract,could ameliorate TPSC senescent phenotypes caused by long-term passage and natural aging in rats and humans,as well as restore the self-renewal and proliferative capacities and tenogenic potential of aged TSPCs.In vivo,the systematic administration of POG or the local delivery of POG nanoparticles functionally rescued endogenous tendon regeneration and repair in aged rats to levels similar to those of normal animals.Mechanistically,POG protects TSPCs against functional impairment during both passage-induced and natural aging by simultaneously suppressing nuclear factor-κB and decreasing mTOR signaling with the induction of autophagy.Thus,the strategy of pharmacological intervention with the deep learning-predicted compound POG could rejuvenate aged TSPCs and improve the regenerative capacity of aged tendons.

Effect of Different Splint Thicknesses on Occlusal Function and Temporomandibular Joint Sounds:A Clinical Report

Background: Occlusal splint therapy, which is a conservative approach to treat temporomandibular disorders (TMDs) and bruxism, can change the occlusal contact of dentition. However, little is known about the variation in bite force and temporomandibular joint (TMJ) sounds. The objective of this case report is to compare the effects of different splint thicknesses constructed by vacuum lamination technology on occlusal function and TMJ sounds. Clinical Presentation: This study presents a 24-year-old male with bruxism. Four splints of different thicknesses (0.6 mm, 1 mm, 2.5 mm and 3 mm) were fabricated and tested. Then, an array of occlusal data were recorded and analyzed by the T-Scan?III system and joint vibration analysis (JVA). Conclusion: The results reveal that splints of different thicknesses manufactured by the vacuum hot-lamination apparatus may cause a change in occlusal force.

Methionine oxidation and reduction of the ethylene signaling component MaEIL9 are involved in banana fruit ripening

The ethylene insensitive 3/ethylene insensitive3-like(EIN3/EIL)plays an indispensable role in fruit ripening.However,the regulatory mechanism that links post-translational modification of EIN3/EIL to fruit ripening is largely unknown.Here,we studied the expression of 13 MaE IL genes during banana fruit ripening,among which MaE IL9 displayed higher enhancement particularly in the ripening stage.Consistent with its transcript pattern,abundance of MaE IL9 protein gradually increased during the ripening process,with maximal enhancement in the ripening.DNA affinity purification(DAP)-seq analysis revealed that MaE IL9 directly targets a subset of genes related to fruit ripening,such as the starch hydrolytic genes MaA MY3D and MaB AM1.Stably overexpressing MaE IL9 in tomato fruit hastened fruit ripening,whereas transiently silencing this gene in banana fruit retarded the ripening process,supporting a positive role of MaEIL9 in fruit ripening.Moreover,oxidation of methionines(Met-129,Met-130,and Met-282)in MaEIL9 resulted in the loss of its DNA-binding capacity and transcriptional activation activity.Importantly,we identified MaEIL9 as a potential substrate protein of methionine sulfoxide reductase A MaMsrA4,and oxidation of Met-129,Met-130,and Met-282in MaEIL9 could be restored by MaMsrA4.Collectively,our findings reveal a novel regulatory network controlling banana fruit ripening,which involves MaMsrA4-mediated redox regulation of the ethylene signaling component MaEIL9.

The SlTPL3–SlWUS module regulates multi-locule formation in tomato by modulating auxin and gibberellin levels in the shoot apical meristem

Malformed fruits depreciate a plant’s market value.In tomato(Solanum lycopersicum),fruit malformation is associated with the multi-locule trait,which involves genes regulating shoot apical meristem(SAM)development.The expression pattern of TOPLESS3(SITPL3)throughout SAM development prompted us to investigate its functional significance via RNA interference(RNAi)and clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9(Cas9)-mediated gene editing.Lower SITPL3 transcript levels resulted in larger fruits with more locules and larger SAMs at the 5 d after germination(DAG5)stage.Differentially expressed genes in the SAM of wild-type(WT)and SITPL3-RNAi plants,identified by transcriptome deep sequencing(RNA-seq),were enriched in the gibberellin(GA)biosynthesis and plant hormone signaling pathways.Moreover,exogenous auxin and paclobutrazol treatments rescued the multi-locule phenotype,indicating that SITPL3 affects SAM size by mediating auxin and GA levels in the SAM.Furthermore,SITPL3 interacted with WUSCHEL(SIWUS),which plays an important role in SAM size maintenance.We conducted RNA-seq and DNA affinity purification followed by sequencing(DAP-seq)analyses to identify the genes regulated by SITPL3 and SIWUS in the SAM and to determine how they regulate SAM size.We detected24 overlapping genes regulated by SITPL3 and SIWUS and harboring an SIWUS-binding motif in their promoters.Furthermore,functional annotation revealed a notable enrichment for functions in auxin transport,auxin signal transduction,and GA biosynthesis.Dual-luciferase assays also revealed that SITPL3 enhances SIWUS-mediated regulation(repression and activation)of SIPIN3 and SIGA2 ox4 transcription,indicating that the SITPL3-SIWUS module regulates SAM size by mediating auxin distribution and GA levels,and perturbations of this module result in enlarged SAM.These results provide novel insights into the molecular mechanism of SAM maintenance and locule formation in tomato and highlight the SITPL3-SIWUS module as a key regulator.