Classification of four distinct osteoarthritis subtypes with a knee joint tissue transcriptome atlas

The limited molecular classifications and disease signatures of osteoarthritis(OA)impede the development of prediagnosis and targeted therapeutics for OA patients.To classify and understand the subtypes of OA,we collected three types of tissue including cartilage,subchondral bone,and synovium from multiple clinical centers and constructed an extensive transcriptome atlas of OA patients.By applying unsupervised clustering analysis to the cartilage transcriptome,OA patients were classified into four subtypes with distinct molecular signatures:a glycosaminoglycan metabolic disorder subtype(C1),a collagen metabolic disorder subtype(C2),an activated sensory neuron subtype(C3),and an inflammation subtype(C4).Through ligand-receptor crosstalk analysis of the three knee tissue types,we linked molecular functions with the clinical symptoms of different OA subtypes.For example,the Gene Ontology functional term of vasculature development was enriched in the subchondral bone-cartilage crosstalk of C2 and the cartilage-subchondral bone crosstalk of C4,which might lead to severe osteophytes in C2 patients and apparent joint space narrowing in C4 patients.Based on the marker genes of the four OA subtypes identified in this study,we modeled OA subtypes with two independent published RNA-seq datasets through random forest classification.The findings of this work contradicted traditional OA diagnosis by medical imaging and revealed distinct molecular subtypes in knee OA patients,which may allow for precise diagnosis and treatment of OA.

Remodeling of the osteoimmune microenvironment after biomaterials implantation in murine tibia: Single-cell transcriptome analysis

Osseointegration seems to be a foreign body reaction equilibrium due to the complicated interactions between the immune and skeletal systems.The heterogeneity of the osteoimmune microenvironment in the osseointegration of implant materials remains elusive.Here,a single-cell study involving 40043 cells is conducted,and a total of 10 distinct cell clusters are identified from five different groups.A preliminary description of the osteoimmune microenvironment revealed the diverse cellular heterogeneity and dynamic changes modulated by implant properties.The increased immature neutrophils,Ly6C+CCR2hi monocytes,and S100a8hi macrophages induce an aggressive inflammatory response and eventually lead to the formation of fibrous capsule around the stainless steel implant.The enrichment of mature neutrophils,FcgR1hi and differentiated immunomodulatory macrophages around the titanium implant indicates favorable osseointegration under moderate immune response.Neutrophil-depletion mice are conducted to explore the role of neutrophils in osseointegration.Neutrophils may improve bone formation by enhancing the recruitment of BMSCs via the CXCL12/CXCR3 signal axis.These findings contribute to a better knowledge of osteoimmunology and are valuable for the design and modification of‘osteoimmune-smart’biomaterials in the bone regeneration field.

Molecular dynamics simulation reveals DNA-specific recognition mechanism via c-Myb in pseudo-palindromic consensus of mim-1 promoter

This study aims to gain insight into the DNA-specific recognition mechanism of c-Myb transcription factor during the regulation of cell early differentiation and proliferation.Therefore,we chose the chicken myeloid gene,mitochondrial import protein 1(mim-1),as a target to study the binding specificity between potential dual-Myb-binding sites.The c-Myb-binding site in mim-1 is a pseudo-palindromic sequence AACGGTT,which contains two AACNG consensuses.Simulation studies in different biological scenarios revealed that c-Myb binding with mim-1 in the forward strand(complex F)is more stable than that in the reverse strand(complex R).The principal component analysis(PCA)dynamics trajectory analyses suggested an opening motion of the recognition helices of R2 and R3(R2R3),resulting in the dissociation of DNA from c-Myb in complex R at 330 K,triggered by the reduced electrostatic potential on the surface of R2R3.Furthermore,the DNA confirmation and hydrogen-bond interaction analyses indicated that the major groove width of DNA increased in complex R,which affected on the hydrogenbond formation ability between R2R3 and DNA,and directly resulted in the dissociation of DNA from R2R3.The steered molecular dynamics(SMD)simulation studies also suggested that the electrostatic potential,major groove width,and hydrogen bonds made major contribution to the DNA-specific recognition.In vitro trials confirmed the simulation results that c-Myb specifically bound to mim-1 in the forward strand.This study indicates that the three-dimensional(3D)structure features play an important role in the DNA-specific recognition mechanism by c-Myb besides the AACNG consensuses,which is beneficial to understanding the cell early differentiation and proliferation regulated by c-Myb,as well as the prediction of novel c-Myb-binding motifs in tumorigenesis.

Tumor-suppressive function and mechanism of HOXB13 in right-sided colon cancer

Right-sided colon cancer(RCC)and left-sided colon cancer(LCC)differ in their clinical and molecular features.An investigation of differentially expressed genes(DEGs)between RCC and LCC could contribute to targeted therapy for colon cancer,especially RCC,which has a poor prognosis.Here,we identified HOXB13,which was significantly less expressed in RCC than in LCC and associated with prognosis in RCC,by using 5 datasets from the Gene Expression Omnibus(GEO).Tissue sample analysis showed that HOXB13 was differentially expressed between normal and only RCC tumor tissues.HOXB13 inhibited colon cancer cell proliferation and induced apoptosis both in vitro and in vivo.Furthermore,we found that HOXB13 might be regulated by DNMT3B and suppress C-myc expression to exert antitumor effects viaβ-catenin/TCF4 signals in RCC.In conclusion,the current study is the first to demonstrate that HOXB13 has a tumor-suppressive effect in RCC.High expression levels of HOXB13 are associated with prolonged overall survival in patients with RCC.The DNMT3B-HOXB13-C-myc signaling axis might be a molecular target for the treatment of RCC.

Erratum to:Molecular dynamics simulation reveals DNA-specific recognition mechanism via c-Myb in pseudo-palindromic consensus of mim-1 promoter

Erratum to:J Zhejiang Univ-Sci B(Biomed&Biotechnol)202324(10):883-895 https://doi.0rg/10.1631/jzus.B2200634.The original version of this article(Weng et al.,2023)unfortunately contained a mistake.In Acknowledgments,the number(No.226-2022-00213)of the Fundamental Research Funds for the Central Universities is wrong.The correct number should be No.2022FZZX01-33.