Osteocyte TGFβ1‑Smad2/3 is positively associated with bone turnover parameters in subchondral bone of advanced osteoarthritis

Dai, Guangming; Xiao, Haozhuo; Liao, Junyi; Zhou, Nina; Zhao, Chen; Xu, Wei; Xu, Wenjuan; Liang, Xi; Huang, Wei

doi:10.3892/ijmm.2020.4576

Cited by 18 publications

(21 citation statements)

References 48 publications

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“… 39 40 In addition, it was confirmed in vitro that transforming growth factor-β1 (TGF-β1) from osteocytes could enhance osteoblast-mediated bone anabolic metabolism by activating Smad2/3 in the subchondral bone in advanced-stage OA. 41 As a result, the concomitant increase in osteoblast activity leads to spatial remineralisation and osteosclerosis in the end stage of OA.…”

Section: Osteoarthritic Subchondral Bone Microenvironmentmentioning

confidence: 99%

Microenvironment in subchondral bone: predominant regulator for the treatment of osteoarthritis

et al. 2020

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Osteoarthritis (OA) is a degenerative joint disease in the elderly. Although OA has been considered as primarily a disease of the articular cartilage, the participation of subchondral bone in the pathogenesis of OA has attracted increasing attention. This review summarises the microstructural and histopathological changes in subchondral bone during OA progression that are due, at the cellular level, to changes in the interactions among osteocytes, osteoblasts, osteoclasts (OCs), endothelial cells and sensory neurons. Therefore, we focus on how pathological cellular interactions in the subchondral bone microenvironment promote subchondral bone destruction at different stages of OA progression. In addition, the limited amount of research on the communication between OCs in subchondral bone and chondrocytes (CCs) in articular cartilage during OA progression is reviewed. We propose the concept of ‘OC–CC crosstalk’ and describe the various pathways by which the two cell types might interact. Based on the ‘OC–CC crosstalk’, we elaborate potential therapeutic strategies for the treatment of OA, including restoring abnormal subchondral bone remodelling and blocking the bridge—subchondral type H vessels. Finally, the review summarises the current understanding of how the subchondral bone microenvironment is related to OA pain and describes potential interventions to reduce OA pain by targeting the subchondral bone microenvironment.

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Section: Osteoarthritic Subchondral Bone Microenvironmentmentioning

confidence: 99%

Microenvironment in subchondral bone: predominant regulator for the treatment of osteoarthritis

et al. 2020

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“…Furthermore, the changes in subchondral bone are related to several signaling pathways such as the Wnt/β-Catenin, TGF-β/Smad, RANK/RANKL/OPG (Receptor activator of nuclear factor kappa-Β, RANK ligand, and osteoprotegerin), and MAPK (mitogen-activated protein kinase) signaling pathways [ 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. Moreover, identification of the molecular pathways involved in OA-related bone remodeling has led to certain therapeutic agents targeting the mechanisms considered as possible DMOADs [ 85 , 86 , 87 , 88 , 89 , 90 ].…”

Section: Therapeutic Approach To Bone Remodeling In Knee Osteoarthmentioning

confidence: 99%

From Pathogenesis to Therapy in Knee Osteoarthritis: Bench-to-Bedside

Rezuş

Burlui

Cardoneanu

et al. 2021

IJMS

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Osteoarthritis (OA) is currently the most widespread musculoskeletal condition and primarily affects weight-bearing joints such as the knees and hips. Importantly, knee OA remains a multifactorial whole-joint disease, the appearance and progression of which involves the alteration of articular cartilage as well as the synovium, subchondral bone, ligaments, and muscles through intricate pathomechanisms. Whereas it was initially depicted as a predominantly aging-related and mechanically driven condition given its clear association with old age, high body mass index (BMI), and joint malalignment, more recent research identified and described a plethora of further factors contributing to knee OA pathogenesis. However, the pathogenic intricacies between the molecular pathways involved in OA prompted the study of certain drugs for more than one therapeutic target (amelioration of cartilage and bone changes, and synovial inflammation). Most clinical studies regarding knee OA focus mainly on improvement in pain and joint function and thus do not provide sufficient evidence on the possible disease-modifying properties of the tested drugs. Currently, there is an unmet need for further research regarding OA pathogenesis as well as the introduction and exhaustive testing of potential disease-modifying pharmacotherapies in order to structure an effective treatment plan for these patients.

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“…During OA development, several molecules have been reported to be involved to mediate TGF-β signaling suppression at a transcriptional level, EZH2 and CaMKII for instance 13 , 14 . However, inconsistency of SMAD2/3 protein and mRNA level was observed in OA as SMAD2/3 protein was down-regulated along with no alteration at mRNA level 11 , 15 , 16 (GSE117999 and GSE110606), which could not be explained by the aforementioned mechanism, and suggested a post-translational regulation, such as microRNAs (miRNAs). miRNAs are a class of endogenous ~22 nt non-coding small RNAs of targeting mRNAs of multiple genes.…”

Section: Introductionmentioning

confidence: 99%

Targeting miR-18a sensitizes chondrocytes to anticytokine therapy to prevent osteoarthritis progression

Lian

Tao

et al. 2020

Cell Death Dis

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Inflammation participates in the development of OA and targeting inflammatory signaling pathways is a potential strategy for OA treatment. IL-1β is one of the most important inflammatory factors to trigger the activation of NF-κB signaling and accelerate OA progression, whereas OA patients could hardly benefit from inhibiting IL-1β in clinic, suggesting the importance to further explore the details of OA inflammation. We here showed that expression of miR-18a in chondrocytes was specifically induced in response to IL-1β in vitro as well as in rat model of OA during which NF-κB signaling was involved, and that nuclear-translocated p65 directly upregulated miR-18a expression at transcriptional level. Further, increased miR-18a mediated hypertrophy of chondrocytes, resulting in OA degeneration, by targeting TGFβ1, SMAD2, and SMAD3 and subsequently leading to repression of TGF-β signaling. And the level of serum miR-18a was positively correlated to severity of OA. Interestingly, other than IL-1β, pro-inflammation cytokines involving TNFα could also remarkably upregulate miR-18a via activating NF-κB signaling and subsequently induce chondrocytes hypertrophy, suggesting a pivotal central role of miR-18a in inflammatory OA progression. Thus, our study revealed a novel convergence of NF-κB and TGF-β signaling mediated by miR-18a, and a novel mechanism underlying inflammation-regulated OA dependent of NF-κB/miR-18a/TGF-β axis. Notably, in vivo assay showed that targeting miR-18a sensitized OA chondrocytes to IL-1β inhibitor as targeting IL-1β and miR-18a simultaneously had much stronger inhibitory effects on OA progression than suppressing IL-1β alone. Therefore, the diagnostic and therapeutic potentials of miR-18a for OA were also revealed.

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Osteocyte TGFβ1‑Smad2/3 is positively associated with bone turnover parameters in subchondral bone of advanced osteoarthritis

Cited by 18 publications

References 48 publications

Microenvironment in subchondral bone: predominant regulator for the treatment of osteoarthritis

Microenvironment in subchondral bone: predominant regulator for the treatment of osteoarthritis

From Pathogenesis to Therapy in Knee Osteoarthritis: Bench-to-Bedside

Targeting miR-18a sensitizes chondrocytes to anticytokine therapy to prevent osteoarthritis progression

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