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1.
Biomolecules ; 13(2)2023 02 17.
Article in English | MEDLINE | ID: mdl-36830751

ABSTRACT

Osteoarthritis (OA) is a painful and disabling joint disease affecting millions worldwide. The lack of clinically relevant models limits our ability to predict therapeutic outcomes prior to clinical trials, where most drugs fail. Therefore, there is a need for a model that accurately recapitulates the whole-joint disease nature of OA in humans. Emerging microphysiological systems provide a new opportunity. We recently established a miniature knee joint system, known as the miniJoint, in which human bone-marrow-derived mesenchymal stem cells (hBMSCs) were used to create an osteochondral complex, synovial-like fibrous tissue, and adipose tissue analogs. In this study, we explored the potential of the miniJoint in developing novel treatments for OA by testing the hypothesis that co-treatment with anti-inflammation and chondroinducing agents can suppress joint inflammation and associated cartilage degradation. Specifically, we created a "synovitis"-relevant OA model in the miniJoint by treating synovial-like tissues with interleukin-1ß (IL-1ß), and then a combined treatment of oligodeoxynucleotides (ODNs) suppressing the nuclear factor kappa beta (NF-κB) genetic pathway and bone morphogenic protein-7 (BMP-7) was introduced. The combined treatment with BMP-7 and ODNs reduced inflammation in the synovial-like fibrous tissue and showed an increase in glycosaminoglycan formation in the cartilage portion of the osteochondral complex. For the first time, this study demonstrated the potential of the miniJoint in developing disease-modifying OA drugs. The therapeutic efficacy of co-treatment with NF-κB ODNs and BMP-7 can be further validated in future clinical studies.


Subject(s)
Bone Morphogenetic Protein 7 , Osteoarthritis , Humans , Pilot Projects , Bone Morphogenetic Protein 7/therapeutic use , NF-kappa B/metabolism , Microphysiological Systems , Cartilage/metabolism , Osteoarthritis/drug therapy
2.
Sci China Life Sci ; 65(2): 309-327, 2022 02.
Article in English | MEDLINE | ID: mdl-34109475

ABSTRACT

Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis (OA). In this study, we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs (DMOADs). Specifically, human bone marrow-derived mesenchymal stromal cells (MSCs) were expanded in vitro up to passage 10 (P10-MSCs). Following their senescent phenotype formation, P10-MSCs were subjected to pellet culture in chondrogenic medium. Results from qRT-PCR, histology, and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents, when compared to that from normal passage 4 (P4)-MSCs. Interestingly, the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples, as demonstrated by RNA Sequencing data and other analysis methods. Lastly, the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics. The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage. The P4- and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.


Subject(s)
Antirheumatic Agents/pharmacology , Cartilage/drug effects , Cellular Senescence/drug effects , Mesenchymal Stem Cells/cytology , Models, Biological , Osteoarthritis/drug therapy , Antirheumatic Agents/therapeutic use , Cartilage/metabolism , Cartilage/pathology , Cell Differentiation , Cells, Cultured , Cellular Senescence/genetics , Chondrocytes/drug effects , Chondrocytes/metabolism , Chondrocytes/pathology , Drug Evaluation, Preclinical , Humans , Mesenchymal Stem Cells/metabolism , Osteoarthritis/metabolism , Osteoarthritis/pathology , Senotherapeutics/pharmacology , Tissue Engineering , Transcriptome
3.
Biomed Mater ; 16(1): 012002, 2020 12 23.
Article in English | MEDLINE | ID: mdl-32906098

ABSTRACT

Mesenchymal stem cell-derived extracellular matrix (mECM) has received increased attention in the fields of tissue engineering and scaffold-assisted regeneration. mECM exhibits many unique characteristics, such as robust bioactivity, biocompatibility, ease of use, and the potential for autologous tissue engineering. As the use of mECM has increased in musculoskeletal tissue engineering, it should be noted that mECM generated from current methods has inherited insufficiencies, such as low mechanical properties and lack of internal architecture. In this review, we first summarize the development and use of mECM as a scaffold for musculoskeletal tissue regeneration and highlight our current progress on moving this technology toward clinical application. Then we review recent methods to improve the properties of mECM that will overcome current weaknesses. Lastly, we propose future studies that will pave the road for mECM application in regenerating tissues in humans.


Subject(s)
Extracellular Matrix/physiology , Mesenchymal Stem Cells/physiology , Musculoskeletal System/injuries , Tissue Engineering/methods , Tissue Scaffolds/chemistry , Animals , Biocompatible Materials/chemistry , Bone Regeneration , Cartilage/injuries , Cartilage/physiology , Cells, Cultured , Extracellular Matrix/chemistry , Humans , Materials Testing , Mesenchymal Stem Cell Transplantation , Musculoskeletal Physiological Phenomena , Regeneration/physiology
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