scholarly journals Post-traumatic osteoarthritis development is not modified by postnatal chondrocyte deletion of CCN2

2020 ◽  
Author(s):  
Craig M Keenan ◽  
Lorenzo Ramos-Mucci ◽  
Ioannis Kanakis ◽  
Peter I Milner ◽  
Andrew Leask ◽  
...  
Keyword(s):  
Articular Chondrocytes ◽  
Cartilage Degeneration ◽  
Knee Joints ◽  
Matricellular Protein ◽  
Non Invasive ◽  
Post Surgery ◽  
Surgical Model ◽  
Summary Statement ◽  
Post Traumatic

AbstractCCN2 is a matricellular protein involved in several critical biological processes. In particular, CCN2 is involved in cartilage development and in osteoarthritis. CCN2 null mice exhibit a range of skeletal dysmorphisms, highlighting its importance in regulating matrix formation during development, however its role in adult cartilage remains unclear. The aim of this study was to determine the role of CCN2 in postnatal chondrocytes in models of post-traumatic osteoarthritis (PTOA). CCN2 deletion was induced in articular chondrocytes of male transgenic mice at 8 weeks of age. PTOA was induced in knees either surgically or non-invasively by repetitive mechanical loading at 10 weeks of age. Knee joints were harvested, scanned with micro-CT, and processed for histology. Sections were stained with toluidine blue and scored using the OARSI grading system. In the non-invasive model cartilage lesions were present in the lateral femur but no significant differences were observed between wildtype (WT) and CCN2 knockout (KO) mice 6 weeks post-loading. In the surgical model, severe cartilage degeneration was observed in the medial compartments but no significant differences were observed between WT and CCN2 KO mice at 2, 4, and 8 weeks post-surgery. We conclude that CCN2 deletion in chondrocytes did not modify the development of PTOA in mice, suggesting that chondrocyte expression of CCN2 in adults is not a critical player in protecting cartilage from the degeneration associated with PTOA.Summary StatementPost-natal deletion of CCN2 in chondrocytes does not affect the development of post-traumatic osteoarthritis in mice.

scholarly journals Post-traumatic osteoarthritis development is not modified by postnatal chondrocyte deletion of Ccn2

2020 ◽  
Vol 13 (7) ◽  
pp. dmm044719 ◽  
Author(s):  
Craig M. Keenan ◽  
Lorenzo Ramos-Mucci ◽  
Ioannis Kanakis ◽  
Peter I. Milner ◽  
Andrew Leask ◽  
...  
Keyword(s):  
Articular Chondrocytes ◽  
Cartilage Degeneration ◽  
Research Society ◽  
Knee Joints ◽  
Matricellular Protein ◽  
Micro Computed Tomography ◽  
Non Invasive ◽  
Post Surgery ◽  
Osteoarthritis Research Society ◽  
Post Traumatic

ABSTRACTCCN2 is a matricellular protein involved in several crucial biological processes. In particular, CCN2 is involved in cartilage development and in osteoarthritis. Ccn2 null mice exhibit a range of skeletal dysmorphisms, highlighting its importance in regulating matrix formation during development; however, its role in adult cartilage remains unclear. The aim of this study was to determine the role of CCN2 in postnatal chondrocytes in models of post-traumatic osteoarthritis (PTOA). Ccn2 deletion was induced in articular chondrocytes of male transgenic mice at 8 weeks of age. PTOA was induced in knees either surgically or non-invasively by repetitive mechanical loading at 10 weeks of age. Knee joints were harvested, scanned with micro-computed tomography and processed for histology. Sections were stained with Toluidine Blue and scored using the Osteoarthritis Research Society International (OARSI) grading system. In the non-invasive model, cartilage lesions were present in the lateral femur, but no significant differences were observed between wild-type (WT) and Ccn2 knockout (KO) mice 6 weeks post-loading. In the surgical model, severe cartilage degeneration was observed in the medial compartments, but no significant differences were observed between WT and Ccn2 KO mice at 2, 4 and 8 weeks post-surgery. We conclude that Ccn2 deletion in chondrocytes does not modify the development of PTOA in mice, suggesting that chondrocyte expression of CCN2 in adults is not a crucial factor in protecting cartilage from the degeneration associated with PTOA.This article has an associated First Person interview with the first author of the paper.

scholarly journals Single-Cell RNA-Seq Reveals Transcriptomic Heterogeneity and Post-Traumatic Osteoarthritis-Associated Early Molecular Changes in Mouse Articular Chondrocytes

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1462
Author(s):  
Aimy Sebastian ◽  
Jillian L. McCool ◽  
Nicholas R. Hum ◽  
Deepa K. Murugesh ◽  
Stephen P. Wilson ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Single Cell ◽  
Articular Chondrocytes ◽  
Cartilage Degeneration ◽  
Cell Types ◽  
Knee Joints ◽  
Molecular Changes ◽  
Post Traumatic ◽  
Joint Trauma ◽  
Functional Profiles

Articular cartilage is a connective tissue lining the surfaces of synovial joints. When the cartilage severely wears down, it leads to osteoarthritis (OA), a debilitating disease that affects millions of people globally. The articular cartilage is composed of a dense extracellular matrix (ECM) with a sparse distribution of chondrocytes with varying morphology and potentially different functions. Elucidating the molecular and functional profiles of various chondrocyte subtypes and understanding the interplay between these chondrocyte subtypes and other cell types in the joint will greatly expand our understanding of joint biology and OA pathology. Although recent advances in high-throughput OMICS technologies have enabled molecular-level characterization of tissues and organs at an unprecedented resolution, thorough molecular profiling of articular chondrocytes has not yet been undertaken, which may be in part due to the technical difficulties in isolating chondrocytes from dense cartilage ECM. In this study, we profiled articular cartilage from healthy and injured mouse knee joints at a single-cell resolution and identified nine chondrocyte subtypes with distinct molecular profiles and injury-induced early molecular changes in these chondrocytes. We also compared mouse chondrocyte subpopulations to human chondrocytes and evaluated the extent of molecular similarity between mice and humans. This work expands our view of chondrocyte heterogeneity and rapid molecular changes in chondrocyte populations in response to joint trauma and highlights potential mechanisms that trigger cartilage degeneration.

scholarly journals Rapamycin microparticles induce autophagy, prevent senescence and are effective in treatment of Osteoarthritis

2021 ◽  
Author(s):  
Kaamini M Dhanabalan ◽  
Ameya A Dravid ◽  
Smriti Agarwal ◽  
Ramanath K Sharath ◽  
Ashok K Padmanabhan ◽  
...  
Keyword(s):  
Articular Chondrocytes ◽  
Symptomatic Relief ◽  
Cartilage Damage ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Cartilage Degeneration ◽  
Current Standard ◽  
Disease Modifying Drugs ◽  
Post Traumatic ◽  
Sulphated Glycosaminoglycans

Trauma to the knee joint is associated with significant cartilage degeneration and erosion of subchondral bone, which eventually leads to osteoarthritis (OA), resulting in substantial morbidity and healthcare burden. With no disease-modifying drugs in clinics, the current standard of care focuses on symptomatic relief and viscosupplementation. Modulation of autophagy and targeting senescence pathways are emerging as potential treatment strategies. Rapamycin has shown promise in OA disease amelioration by autophagy upregulation, yet its clinical use is hindered by difficulties in achieving therapeutic concentrations, necessitating multiple weekly injections. Here, we have synthesized rapamycin - loaded poly (lactic-co-glycolic acid) microparticles (RMPs) that induced autophagy, prevented senescence and sustained sulphated glycosaminoglycans(sGAG) production in primary human articular chondrocytes from OA patients. RMPs were potent, nontoxic, and exhibited high retention time (up to 35 days) in mice joints. Intra-articular delivery of RMPs effectively mitigated cartilage damage and inflammation in surgery-induced OA when administered as a prophylactic or therapeutic regimen. Together, our studies demonstrate the feasibility of using RMPs as a potential clinically translatable therapy to prevent and treat post-traumatic osteoarthritis.

scholarly journals Suppressed Osteocyte Perilacunar / Canalicular Remodeling Plays a Causal Role in Osteoarthritis

2019 ◽  
Author(s):  
Courtney M. Mazur ◽  
Jonathon J. Woo ◽  
Cristal S. Yee ◽  
Aaron J. Fields ◽  
Claire Acevedo ◽  
...  
Keyword(s):  
Subchondral Bone ◽  
Cartilage Degeneration ◽  
Causal Role ◽  
Knee Joints ◽  
Cellular Mechanisms ◽  
Primary Disorder ◽  
End Stage ◽  
Early Oa ◽  
Protease Expression

ABSTRACTOsteoarthritis (OA), long considered a primary disorder of articular cartilage, is commonly associated with subchondral bone sclerosis. However, the cellular mechanisms responsible for changes to subchondral bone in OA, and the extent to which these changes are drivers of or a secondary reaction to cartilage degeneration, remain unclear. In knee joints from human patients with end-stage OA, we found evidence of profound defects in osteocyte function. Suppression of osteocyte perilacunar/canalicular remodeling (PLR) was most severe in OA subchondral bone, with lower protease expression, diminished canalicular networks, and disorganized and hypermineralized extracellular matrix. To determine if PLR suppression plays a causal role in OA, we ablated the PLR enzyme MMP13 in osteocytes, while leaving chondrocytic MMP13 intact. Not only did osteocytic MMP13 deficiency suppress PLR in cortical and subchondral bone, but it also compromised cartilage. Even in the absence of injury, this osteocyte-intrinsic PLR defect was sufficient to reduce cartilage proteoglycan content and increase the incidence of cartilage lesions, consistent with early OA. Thus, in humans and mice, osteocyte PLR is a critical regulator of cartilage homeostasis. Together, these findings implicate osteocytes in bone-cartilage crosstalk in the joint and identify the causal role of suppressed perilacunar/canalicular remodeling in osteoarthritis.

scholarly journals Initial effects of inflammation-related cytokines and signaling pathways on the pathogenesis of post-traumatic osteoarthritis

2018 ◽  
Vol 5 (2) ◽  
pp. 91-96
Author(s):  
Peng-Fei Han ◽  
Zhi-Liang Zhang ◽  
Tao-Yu Chen ◽  
Rui-Peng Zhao ◽  
Rong Zhang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Cartilage Degeneration ◽  
Pathological Process ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Post Traumatic ◽  
Multiple Signaling ◽  
The Relationship ◽  
And Oxidative Stress

Abstract The main pathological change in post-traumatic osteoarthritis (PTOA) is cartilage degeneration, which is closely related to inflammation and oxidative stress. Inflammation can cause degeneration of articular cartilage. Cartilage degeneration can also stimulate the progression of inflammation. It has been found that inflammatory cytokines can participate in the pathological process of cartilage degeneration through multiple signaling pathways, mainly mitogen-activated protein kinase, nuclear transcription factor kappa B, and Wnt–β-catenin signal transduction pathways. This review aimed at exploring the relationship between PTOA and inflammation-related cytokines by introducing the role of proinflammatory cytokines in chondrocyte destruction and extracellular matrix degradation.

scholarly journals Periostin loss-of-function protects mice from post-traumatic and age-related osteoarthritis

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Mukundan Attur ◽  
Xin Duan ◽  
Lei Cai ◽  
Tianzhen Han ◽  
Weili Zhang ◽  
...  
Keyword(s):  
Serum Levels ◽  
Cartilage Degeneration ◽  
Rna Seq ◽  
Loss Of Function ◽  
Age Related ◽  
Synovial Lining Cell ◽  
Bone Changes ◽  
Post Traumatic ◽  
Old Mice

Abstract Background Elevated levels of periostin (Postn) in the cartilage and bone are associated with osteoarthritis (OA). However, it remains unknown whether Postn loss-of-function can delay or prevent the development of OA. In this study, we sought to better understand the role of Postn in OA development and assessed the functional impact of Postn deficiency on post-traumatic and age-related OA in mice. Methods The effects of Postn deficiency were studied in two murine experimental OA models using Postn−/− (n = 32) and littermate wild-type (wt) mice (n = 36). Post-traumatic OA was induced by destabilization of the medial meniscus (DMM) in 10-week-old mice (n = 20); age-related OA was analyzed in 24-month-old mice (n = 13). Cartilage degeneration was assessed histologically using the OARSI scoring system, and synovitis was evaluated by measuring the synovial lining cell layer and the cells density in the synovial stroma. Bone changes were measured by μCT analysis. Serum levels of Postn were determined by ELISA. Expression of Postn and collagenase-3 (MMP-13) was measured by immunostaining. RNA-seq was performed on chondrocytes isolated from 21-day old Postn−/− (n = 3) and wt mice (n = 3) to discover genes and pathways altered by Postn knockout. Results Postn−/− mice exhibited significantly reduced cartilage degeneration and OARSI score relative to wt mice in post-traumatic OA after 8 weeks (maximum: 2.37 ± 0.74 vs. 4.00 ± 1.20, P = 0.011; summed: 9.31 ± 2.52 vs. 21.44 ± 6.01, P = 0.0002) and spontaneous OA (maximum: 1.93 ± 0.45 vs. 3.58 ± 1.16, P = 0.014; summed: 6.14 ± 1.57 vs. 11.50 ± 3.02, P = 0.003). Synovitis was significantly lower in Postn−/− mice than wt only in the DMM model (1.88 ± 1.01 vs. 3.17 ± 0.63; P = 0.039). Postn−/− mice also showed lower trabecular bone parameters such as BV/TV, vBMD, Tb.Th, and Tb.N and high Tb. Sp in both models. Postn−/− mice had negligible levels of serum Postn compared with wt. Immunofluorescent studies of cartilage indicated that Postn−/− mice expressed lower MMP-13 levels than wt mice. RNA-seq revealed that cell-cell-adhesion and cell-differentiation processes were enriched in Postn−/− mice, while those related to cell-cycle and DNA-repair were enriched in wt mice. Conclusions Postn deficiency protects against DMM-induced post-traumatic and age-related spontaneous OA. RNA-seq findings warrant further investigations to better understand the mechanistic role of Postn and its potential as a therapeutic target in OA.

scholarly journals Robust Characterization of Non-Invasive Post-Traumatic Osteoarthritis Mouse Model

2021 ◽  
Author(s):  
Fazal-Ur-Rehman Bhatti ◽  
Yong-Hoon Jeong ◽  
Do-Gyoon Kim ◽  
David D Brand ◽  
Karen A Hasty ◽  
...  
Keyword(s):  
Mouse Model ◽  
Knee Joint ◽  
Mouse Models ◽  
Mechanical Loading ◽  
Left Knee ◽  
Knee Joints ◽  
Control Group ◽  
Molecular Changes ◽  
Non Invasive ◽  
Post Traumatic

Objective: Biochemical and molecular changes involved in the pathophysiology of post-traumatic arthritis (PTOA) have not been fully understood. This study used non-invasive mouse models to study biochemical, biomechanical and pain-related behavior changes induced in mice following repetitive mechanical knee loading. Mouse models were used to reflect the effects of the early stages of PTOA in humans. Methods: Forty-eight twelve week old male mice were obtained for three groups: normal control without mechanical loading, trauma (24 hours after loading), and PTOA (early OA) groups. For the non-invasive PTOA mouse model, cyclic comprehensive loading (9 N) was applied on the left knee joint of each mouse. Biochemical and molecular changes induced by mechanical loading were analyzed after loading was completed. Blood and cartilage were collected and further examined using gene expression analysis. Grading of the tissue sections was completed using the osteoarthritis research society international (OARSI) scale. Biomechanical features of mechanically loaded knee joints were determined after 24 hours (Trauma) and three weeks (PTOA) post-mechanical loading sessions to examine the development of PTOA, respectively. Results: The loaded left knee joint showed a greater ROS/RNS signal than the right knee that was not loaded. There was an increase in cartilage damage and MMP activity in the affected knee as the intensity of MabCII680 and MMP750 signal increased in the mechanical loaded joints as compared to unloaded control knee joints. There was also an increase in the difference of viscoelastic energy dissipation ability (tan δ) in PTOA. The OA score increased significantly in mechanically loaded knee joints. Conclusion: This study showed that biomechanical, biochemical, and behavioral characteristics of the murine PTOA groups are significantly different from the control group. These results validate that the current mouse model can be used for translational studies to examine PTOA.

scholarly journals Pink1-Mediated Chondrocytic Mitophagy Contributes to Cartilage Degeneration in Osteoarthritis

2019 ◽  
Vol 8 (11) ◽  
pp. 1849 ◽  
Author(s):  
Hyo Jung Shin ◽  
Hyewon Park ◽  
Nara Shin ◽  
Hyeok Hee Kwon ◽  
Yuhua Yin ◽  
...  
Keyword(s):  
Cell Death ◽  
Articular Chondrocytes ◽  
Mitochondrial Fission ◽  
Cartilage Damage ◽  
Cartilage Degeneration ◽  
Osteoarthritic Cartilage ◽  
Monosodium Iodoacetate ◽  
Biochemical Mechanisms ◽  
Related Proteins

Cartilage loss is a central event in the pathogenesis of osteoarthritis (OA), though other than mechanical loading, the biochemical mechanisms underlying OA pathology remain poorly elucidated. We investigated the role of Pink1-mediated mitophagy in mitochondrial fission, a crucial process in OA pathogenesis. We used a monosodium iodoacetate (MIA)-induced rodent model of OA, which inhibits the activity of articular chondrocytes, leading to disruption of glycolytic energy metabolism and eventual cell death. The OA rat cartilage exhibits significant induction of autophagy-related proteins LC3B and p62, similar to human osteoarthritic cartilage. Moreover, expression of Pink1 and Parkin proteins were also increased in OA. Here, we confirm that Pink1-mediated mitophagy leads to cell death in chondrocytes following MIA treatment, while deficiency in Pink1 expression was associated with decreased cartilage damage and pain behaviors in MIA-induced OA. Finally, we found that autophagy and mitophagy-related genes are highly expressed in human osteoarthritic cartilage. These results indicate that OA is a degenerative condition associated with mitophagy, and suggest that targeting the Pink1 pathway may provide a therapeutic avenue for OA treatment.

scholarly journals OP0202 STRESS-ACTIVATED MIR-204 GOVERNS SENESCENT PHENOTYPES OF CHONDROCYTES TO PROMOTE OSTEOARTHRITIS DEVELOPMENT

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 126.3-126
Author(s):  
Y. Cho ◽  
D. Kang ◽  
J. H. Kim
Keyword(s):  
Ectopic Expression ◽  
Cartilage Degeneration ◽  
Cartilage Destruction ◽  
Knee Joints ◽  
Multiple Components ◽  
Post Traumatic ◽  
Matrix Metabolism ◽  
In Vivo Effects ◽  
Surgically Induced

Background:A progressive loss of cartilage matrix leads to the development of osteoarthritis (OA). Matrix homeostasis is disturbed in OA cartilage as the result of reduced production of cartilage-specific matrix and increased secretion of catabolic mediators by chondrocytes. Chondrocyte senescence is a crucial cellular event contributing to such imbalance in matrix metabolism during OA development.Objectives:We sought to identify a previously unknown, senescence-associated signaling pathway in chondrocytes linked to major OA cartilage manifestations such as PG loss and cartilage degeneration.Methods:We particularly aimed to screen miRNAs whose inhibition could effectively modulate senescent phenotypes of chondrocytes to treat OA. We investigated the regulatory mechanisms of miR-204 under various stress-eliciting stimuli in primary cultured human and mouse chondrocytes. We examined the in vivo effects of miR-204 overexpression and its antagonism in surgically induced OA mouse models. DMM surgery was used to induce posttraumatic OA in 12-week-old mice. Small RNAs were delivered to mouse knee joints by intra-articular injection. Various OA manifestations including cartilage destruction, subchondral bone sclerosis, osteophyte maturity, and synovial inflammation in mice were histologically inspected.Results:We identify miR-204 as a senescence-associated microRNA (miRNA) which is markedly upregulated in OA cartilage. The upregulated miR-204 simultaneously targets multiple components of the sulfated proteoglycan (PG) biosynthesis pathway, effectively shutting down PG anabolism. Ectopic expression of the miR-204 in joints triggers spontaneous cartilage loss and OA development, whereas inhibition of miR-204 ameliorates experimental OA, with concomitant recovery of PG synthesis and suppression of inflammatory senescence-associated secretory phenotype (SASP) factors in cartilageConclusion:we unravel a stress-activated senescence pathway that underlies disrupted matrix homeostasis in OA cartilage.References:[1]O. H. Jeon, C. Kim, R.-M. Laberge, M. Demaria, S. Rathod, A. P. Vasserot, J. W. Chung, D. H. Kim, Y. Poon, N. David, D. J. Baker, J. M. van Deursen, J. Campisi, J. H. Elisseeff, Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017)Disclosure of Interests:None declared

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