scholarly journals Loss of mutual protection between human osteoclasts and chondrocytes in damaged joints initiates osteoclast-mediated cartilage degradation by MMPs

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Quitterie C. Larrouture ◽  
Adam P. Cribbs ◽  
Srinivasa R. Rao ◽  
Martin Philpott ◽  
Sarah J. Snelling ◽  
...  
Keyword(s):  
Bone Sarcoma ◽  
Cartilage Degeneration ◽  
Cartilage Degradation ◽  
Osteoclast Formation ◽  
Marker Genes ◽  
Dependent Manner ◽  
Protective Effects ◽  
Human Cartilage ◽  
New Therapeutic Approaches ◽  
Human Osteoclasts

AbstractOsteoclasts are multinucleated, bone-resorbing cells. However, they also digest cartilage during skeletal maintenance, development and in degradative conditions including osteoarthritis, rheumatoid arthritis and primary bone sarcoma. This study explores the mechanisms behind the osteoclast–cartilage interaction. Human osteoclasts differentiated on acellular human cartilage expressed osteoclast marker genes (e.g. CTSK, MMP9) and proteins (TRAP, VNR), visibly damaged the cartilage surface and released glycosaminoglycan in a contact-dependent manner. Direct co-culture with chondrocytes during differentiation increased large osteoclast formation (p < 0.0001) except when co-cultured on dentine, when osteoclast formation was inhibited (p = 0.0002). Osteoclasts cultured on dentine inhibited basal cartilage degradation (p = 0.012). RNA-seq identified MMP8 overexpression in osteoclasts differentiated on cartilage versus dentine (8.89-fold, p = 0.0133), while MMP9 was the most highly expressed MMP. Both MMP8 and MMP9 were produced by osteoclasts in osteosarcoma tissue. This study suggests that bone-resident osteoclasts and chondrocytes exert mutually protective effects on their ‘native’ tissue. However, when osteoclasts contact non-native cartilage they cause degradation via MMPs. Understanding the role of osteoclasts in cartilage maintenance and degradation might identify new therapeutic approaches for pathologies characterized by cartilage degeneration.

scholarly journals Loss of mutually protective effects between osteoclasts and chondrocytes in damaged joints drives osteoclast-mediated cartilage degradation via matrix metalloproteinases

2021 ◽  
Author(s):  
Quitterie C Larrouture ◽  
Adam P Cribbs ◽  
Sarah J Snelling ◽  
Helen J Knowles
Keyword(s):  
Osteoclast Differentiation ◽  
Cartilage Degeneration ◽  
Cartilage Degradation ◽  
Osteoclast Formation ◽  
Marker Genes ◽  
Protective Effects ◽  
Human Cartilage ◽  
Mmp Inhibitor ◽  
Multinucleated Cells ◽  
Bone Sarcomas

AbstractOsteoclasts are large multinucleated cells that resorb bone to regulate bone remodelling during skeletal maintenance and development. It is overlooked that osteoclasts also digest cartilage during this process, as well as in degradative conditions including osteoarthritis, rheumatoid arthritis and primary bone sarcomas such as giant cell tumour of bone. This study explores the poorly understood mechanisms behind the interaction between osteoclasts and cartilage. Morphologically, osteoclasts differentiated on acellular human cartilage formed multinucleated cells expressing characteristic osteoclast marker genes (e.g. CTSK, MMP9) and proteins (TRAP, VNR) that visibly damaged the cartilage surface by SEM, but without the formation of resorption pits. Osteoclasts caused increased glycosaminoglycan (GAG) release from acellular and cellular human cartilage that was dependent on direct contact with the substrate. Direct co-culture with chondrocytes during osteoclast differentiation increased the number of large osteoclasts formed. When osteoclasts were cultured on dentine, direct co-culture with chondrocytes inhibited osteoclast formation and reduced basal degradation of cartilage. This suggests a mutually protective effect on their ‘native’ tissue between bone-resident osteoclasts and chondrocytes, that is reversed when the joint structure breaks down and osteoclasts are in contact with non-native substrates. Mechanistically, osteoclast-mediated cartilage degradation was inhibited by the pan-MMP inhibitor GM6001 and by TIMP1, indicative of a role for soluble MMPs. RNA sequencing and RT-qPCR analysis identified MMP8 as overexpressed in osteoclasts differentiated on cartilage versus dentine, while MMP9 was the most highly expressed MMP on both substrates. Inhibition of either MMP8 or MMP9 by siRNA in mature osteoclasts reduced GAG release, confirming their involvement in cartilage degradation. Immunohistochemical expression of MMP8 and MMP9 was evident in osteoclasts in osteosarcoma tissue sections. Understanding and controlling the activity of osteoclasts might represent a new therapeutic approach for pathologies characterized by cartilage degeneration and presents an attractive target for further research.

scholarly journals Evaluation of CCL21 role in post-knee injury inflammation and early cartilage degeneration

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0247913
Author(s):  
Mohan Subburaman ◽  
Bouchra Edderkaoui
Keyword(s):  
Chemokine Receptors ◽  
Knee Injury ◽  
Expression Profiles ◽  
Neutralizing Antibody ◽  
Cartilage Degeneration ◽  
Cartilage Degradation ◽  
Mrna Levels ◽  
New Therapeutic Approaches ◽  
Post Surgery ◽  
Medial Meniscectomy

The expression of some chemokines and chemokine receptors is induced during the development of post-traumatic osteoarthritis (PTOA), but their involvement in the pathogenesis of the disease is unclear. The goal of this study was to test whether CCL21 and CXCL13 play a role in PTOA development. For this purpose, we evaluated the expression profiles of the chemokines Ccl21 and Cxcl13, matrix metalloproteinase enzymes Mmp3 and Mmp13, and inflammatory cell markers in response to partial medial meniscectomy and destabilization (MMD). We then assessed the effect of local administration of CCL21 neutralizing antibody on PTOA development and post-knee injury inflammation. The mRNA expression of both Ccl21 and Cxcl13 was induced early post-surgery, but only Ccl21 mRNA levels remained elevated 4 weeks post-surgery in rat MMD-operated knees compared to controls. This suggests that while both CXCL13 and CCL21 are involved in post-surgery inflammation, CCL21 is necessary for development of PTOA. A significant increase in the mRNA levels of Cd4, Cd8 and Cd20 was observed during the first 3 days post-surgery. Significantly, treatment with CCL21 antibody reduced post-surgical inflammation that was accompanied by a reduction in the expression of Mmp3 and Mmp13 and post-MMD cartilage degradation. Our findings are consistent with a role for CCL21 in mediating changes in early inflammation and subsequent cartilage degeneration in response to knee injury. Our results suggest that targeting CCL21 signaling pathways may yield new therapeutic approaches effective in delaying or preventing PTOA development following injury.

scholarly journals Macrophage colony-stimulating factor induces substantial osteoclast generation and bone resorption in human bone marrow cultures

Blood ◽  
1996 ◽  
Vol 88 (7) ◽  
pp. 2531-2540 ◽  
Author(s):  
U Sarma ◽  
AM Flanagan
Keyword(s):  
Bone Resorption ◽  
Vitamin D3 ◽  
Osteoclast Formation ◽  
Dependent Manner ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Human Osteoclasts ◽  
Stimulating Factor

Macrophage colony-stimulating factor (M-CSF) is essential for murine osteoclast formation and its role in human hematopoiesis in vitro is not fully defined. Therefore, we have investigated the effect of M-CSF on the formation of human osteoclasts in vitro. M-CSF was found to induce substantial bone resorption and osteoclast formation in a dose-responsive and time-dependent manner above that induced by 1,25 dihydroxyvitamin D3 (1,25 vitamin D3) in cultures of human bone marrow (BM) stromal cells sedimented onto devitalized bone. By day 14 there was a mean of approximately 50% of the surfaces of the bone slices resorbed compared with only 6% in cultures treated with 1,25 vitamin D3 alone. Osteoclasts were identified as 23c6+ cells (an antibody that recognizes the vitronectin receptor), 87.5% of which coexpressed the calcitonin receptor. The number of 23c6+ cells correlated strongly with bone resorption spatially, and in a dose-responsive and time-dependent manner; the correlation coefficient in cultures treated with 1,25 vitamin D3 alone was 0.856 and those treated with both M-CSF and 1,25 vitamin D3 was 0.880. Granulocyte-macrophage colony-stimulating factor, IL-1 beta, IL-3, IL-6, tumor necrosis factor-alpha, transforming growth factor-beta, leukemia inhibitory factor, and IL-11 did not increase bone resorption above that in 1,25 vitamin D3-treated cultures. We also found that 1,25 vitamin D3 increased, to a minor but significant degree, both bone resorption and the concentration of M-CSF in the culture supernatants above that in vehicle-treated cultures, indicating that M-CSF is present in our BM cultures, but that there is insufficient to induce substantial osteoclast formation. These results define a critical role for M-CSF in the formation of human osteoclasts.

scholarly journals Osteoking Decelerates Cartilage Degeneration in DMM-Induced Osteoarthritic Mice Model Through TGF-β/smad-dependent Manner

2021 ◽  
Vol 12 ◽  
Author(s):  
Houfu Ling ◽  
Qinghe Zeng ◽  
Qinwen Ge ◽  
Jiali Chen ◽  
Wenhua Yuan ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Signaling Pathway ◽  
Subchondral Bone ◽  
Cartilage Degeneration ◽  
Cartilage Degradation ◽  
Common Disease ◽  
Dependent Manner ◽  
Wild Type ◽  
Bone Sclerosis

Osteoarthritis (OA) is a common disease characterized by cartilage degeneration. In recent years much attention has been paid to Traditional Chinese Medicine (TCM) since its treatments have shown efficacy for ameliorating cartilage degradation with mild side effects. Osteoking is a TCM prescription that has long been used in OA treatment. However, the exact mechanism of Osteoking are not fully elucidated. In the current study, destabilization of the medial meniscus (DMM)-induced OA mice was introduced as a wild type animal model. After 8 weeks of administration of Osteoking, histomorphometry, OARSI scoring, gait analysis, micro-CT, and immunohistochemical staining for Col2, MMP-13, TGFβRII and pSmad-2 were conducted to evaluate the chondroprotective effects of Osteoking in vivo. Further in vitro experiments were then performed to detect the effect of Osteoking on chondrocytes. TGFβRIICol2ER transgenic mice were constructed and introduced in the current study to validate whether Osteoking exerts its anti-OA effects via the TGF-β signaling pathway. Results demonstrated that in wild type DMM mice, Osteoking ameliorated OA-phenotype including cartilage degradation, subchondral bone sclerosis, and gait abnormality. Col2, TGFβRII, and pSmad-2 expressions were also found to be up-regulated after Osteoking treatment, while MMP-13 was down-regulated. In vitro, the mRNA expression of MMP-13 and ADAMTS5 decreased and the mRNA expression of Aggrecan, COL2, and TGFβRII were up-regulated after the treatment of Osteoking in IL-1β treated chondrocytes. The additional treatment of SB505124 counteracted the positive impact of Osteoking on primary chondrocytes. In TGFβRIICol2ER mice, spontaneous OA-liked phenotype was observed and treatment of Osteoking failed to reverse the OA spontaneous progression. In conclusion, Osteoking ameliorates OA progression by decelerating cartilage degradation and alleviating subchondral bone sclerosis partly via the TGF-β signaling pathway.

scholarly journals Metformin limits osteoarthritis development and progression through activation of AMPK signalling

2020 ◽  
Vol 79 (5) ◽  
pp. 635-645 ◽  
Author(s):  
Jun Li ◽  
Bin Zhang ◽  
Wei-Xiao Liu ◽  
Ke Lu ◽  
Haobo Pan ◽  
...  
Keyword(s):  
Cartilage Degeneration ◽  
Cartilage Degradation ◽  
Research Society ◽  
Cartilage Tissue ◽  
Protective Effects ◽  
Joint Injury ◽  
Synovial Hyperplasia ◽  
Medial Meniscectomy ◽  
Osteoarthritis Research Society ◽  
Amp Activated Protein Kinase

ObjectivesIn this study, we aim to determine the effect of metformin on osteoarthritis (OA) development and progression.MethodsDestabilisation of the medial meniscus (DMM) surgery was performed in 10-week-old wild type and AMP-activated protein kinase (AMPK)α1 knockout (KO) mice. Metformin (4 mg/day in drinking water) was given, commencing either 2 weeks before or 2 weeks after DMM surgery. Mice were sacrificed 6 and 12 weeks after DMM surgery. OA phenotype was analysed by micro-computerised tomography (μCT), histology and pain-related behaviour tests. AMPKα1 (catalytic alpha subunit of AMPK) expression was examined by immunohistochemistry and immunofluorescence analyses. The OA phenotype was also determined by μCT and MRI in non-human primates.ResultsMetformin upregulated phosphorylated and total AMPK expression in articular cartilage tissue. Mild and more severe cartilage degeneration was observed at 6 and 12 weeks after DMM surgery, evidenced by markedly increased Osteoarthritis Research Society International scores, as well as reduced cartilage areas. The administration of metformin, commencing either before or after DMM surgery, caused significant reduction in cartilage degradation. Prominent synovial hyperplasia and osteophyte formation were observed at both 6 and 12 weeks after DMM surgery; these were significantly inhibited by treatment with metformin either before or after DMM surgery. The protective effects of metformin on OA development were not observed in AMPKα1 KO mice, suggesting that the chondroprotective effect of metformin is mediated by AMPK signalling. In addition, we demonstrated that treatment with metformin could also protect from OA progression in a partial medial meniscectomy animal model in non-human primates.ConclusionsThe present study suggests that metformin, administered shortly after joint injury, can limit OA development and progression in injury-induced OA animal models.

scholarly journals RETRACTED ARTICLE: Chondro-protective effects of polydatin in osteoarthritis through its effect on restoring dysregulated autophagy via modulating MAPK, and PI3K/Akt signaling pathways

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Zhengyuan Wu ◽  
Zhiwei Luan ◽  
Xiaohan Zhang ◽  
Kai Zou ◽  
Shiting Ma ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Cartilage Degeneration ◽  
Cartilage Degradation ◽  
Akt Signaling ◽  
Protective Effects ◽  
Mediating Role ◽  
Retracted Article ◽  
Underlying Mechanisms

Abstract Osteoarthritis (OA) is a degenerative disease of the cartilage that is prevalent in the middle-aged and elderly demography. Polydatin (PD), a natural resveratrol glucoside, has shown significant anti-inflammatory and anti-arthritic potential in previous studies. This study was designed to evaluate the therapeutic properties of PD in vitro and in vivo, and elucidate their underlying mechanisms. The expression levels of all relevant factors were evaluated by qRT-PCR, western blotting, and immunohistochemistry (IHC) where suitable. Reactive oxygen species (ROS) and apoptosis were analyzed using the suitable probes and flow cytometry. The histological evidence of cartilage was assessed in rat models, moreover, the several serum cytokines levels and autophagy levels were evaluated. The result showed PD displayed significant chondro-protective effects, inferred in terms of reduced inflammation and cartilage degradation, apoptosis inhibition, and lower ROS production. The protective effects were attenuated by the autophagy inhibitor 3-MA, indicating a mediating role of autophagy in PD action. Mechanistically, PD exerted its effects by inhibiting the MAPK and PI3K/Akt signaling pathways which led to the down-regulation of mTOR. In conclusion, PD protects against cartilage degeneration by activating the autophagy flux in the chondrocytes via the MAPK and PI3K/Akt signaling pathways.

scholarly journals Kartogenin prevents cartilage degradation and alleviates osteoarthritis progression in mice via the miR-146a/NRF2 axis

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Mingzhuang Hou ◽  
Yijian Zhang ◽  
Xinfeng Zhou ◽  
Tao Liu ◽  
Huilin Yang ◽  
...  
Keyword(s):  
Subchondral Bone ◽  
Cartilage Degeneration ◽  
Cartilage Degradation ◽  
Cartilage Matrix ◽  
Related Factor ◽  
Dependent Manner ◽  
Matrix Degradation ◽  
Protein Levels ◽  
Bone Sclerosis

AbstractOsteoarthritis (OA) is a common articular degenerative disease characterized by loss of cartilage matrix and subchondral bone sclerosis. Kartogenin (KGN) has been reported to improve chondrogenic differentiation of mesenchymal stem cells. However, the therapeutic effect of KGN on OA-induced cartilage degeneration was still unclear. This study aimed to explore the protective effects and underlying mechanisms of KGN on articular cartilage degradation using mice with post-traumatic OA. To mimic the in vivo arthritic environment, in vitro cultured chondrocytes were exposed to interleukin-1β (IL-1β). We found that KGN barely affected the cell proliferation of chondrocytes; however, KGN significantly enhanced the synthesis of cartilage matrix components such as type II collagen and aggrecan in a dose-dependent manner. Meanwhile, KGN markedly suppressed the expression of matrix degradation enzymes such as MMP13 and ADAMTS5. In vivo experiments showed that intra-articular administration of KGN ameliorated cartilage degeneration and inhibited subchondral bone sclerosis in an experimental OA mouse model. Molecular biology experiments revealed that KGN modulated intracellular reactive oxygen species in IL-1β-stimulated chondrocytes by up-regulating nuclear factor erythroid 2-related factor 2 (NRF2), while barely affecting its mRNA expression. Microarray analysis further revealed that IL-1β significantly up-regulated miR-146a that played a critical role in regulating the protein levels of NRF2. KGN treatment showed a strong inhibitory effect on the expression of miR-146a in IL-1β-stimulated chondrocytes. Over-expression of miR-146a abolished the anti-arthritic effects of KGN not only by down-regulating the protein levels of NRF2 but also by up-regulating the expression of matrix degradation enzymes. Our findings demonstrate, for the first time, that KGN exerts anti-arthritic effects via activation of the miR-146a-NRF2 axis and KGN is a promising heterocyclic molecule to prevent OA-induced cartilage degeneration.

scholarly journals Ameliorative Effects of Loganin on Arthritis in Chondrocytes and Destabilization of the Medial Meniscus-Induced Animal Model

2021 ◽  
Vol 14 (2) ◽  
pp. 135
Author(s):  
Eunkuk Park ◽  
Chang Gun Lee ◽  
Seung Hee Yun ◽  
Seokjin Hwang ◽  
Hyoju Jeon ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Medial Meniscus ◽  
Bioactive Compound ◽  
Cartilage Degeneration ◽  
Cartilage Degradation ◽  
Protective Effects ◽  
Matrix Metalloproteinase 3 ◽  
Cox 2

Arthritis is a common inflammatory disease that causes pain, stiffness, and joint swelling. Here, we investigated the ameliorative effects of loganin on arthritis in vitro and in vivo. A single bioactive compound was fractionated and isolated from Cornus officinalis (CO) extract to screen for anti-arthritic effects. A single component, loganin, was identified as a candidate. The CO extract and loganin inhibited the expression of factors associated with cartilage degradation, such as cyclooxygenase-2 (COX-2), matrix metalloproteinase 3 (MMP-3), and matrix metalloproteinase 13 (MMP-13), in interukin-1 beta (IL-1β)-induced chondrocyte inflammation. In addition, prostaglandin and collagenase levels were reduced following treatment of IL-1β-induced chondrocytes with loganin. In the destabilization of the medial meniscus (DMM)-induced mouse model, loganin administration attenuated cartilage degeneration by inhibiting COX-2, MMP-3, and MMP-13. Transverse micro-CT images revealed that loganin reduced DMM-induced osteophyte formation. These results indicate that loganin has protective effects in DMM-induced mice.

scholarly journals Trans-Cinnamaldehyde Inhibits IL-1β-Stimulated Inflammation in Chondrocytes by Suppressing NF-κB and p38-JNK Pathways and Exerts Chondrocyte Protective Effects in a Rat Model of Osteoarthritis

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Tianwei Xia ◽  
Runzi Gao ◽  
Guowei Zhou ◽  
Jinzhu Liu ◽  
Jinsheng Li ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cartilage Degradation ◽  
Cartilage Destruction ◽  
Dependent Manner ◽  
Protective Effects ◽  
Monosodium Iodoacetate ◽  
Anti Inflammatory ◽  
Inflammatory Effect

Objective. Trans-cinnamaldehyde (TCA), a compound from Cinnamomum cassia Presl, has been reported to have anti-inflammatory effect. However, its effect on cartilage degradation in osteoarthritis is unclear. This study is designed to examine the effects of TCA on cartilage in vitro and in vivo. Material and Methods. SW1353 cells and human primary chondrocytes were treated with varying concentrations of TCA (2-20 μg/ml) for 2 h followed by IL-1β stimulation. Cell viability was examined by the MTT assay. Expression of MMP-1, MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5 was examined by Western blot and RT-qPCR. Monosodium iodoacetate (MIA)-induced OA was established in rats to assess the chondrocyte protective effects of intraperitoneal injection of TCA (50 mg/kg). Results. TCA at a concentration of 10 μg/ml had no significant effect on cell viability. MMP-1, MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5 were decreased by TCA 2-10 μg/ml in a dose-dependent manner (all P<0.05). Pretreatment with TCA decreased the degradation of IκBα and increased the expression of p-IκBα, indicating that NF-κB inactivation was induced by TCA in IL-1β-stimulated SW1353 cells. Pretreatment with TCA decreased the levels of p-p38 and p-JNK, while the levels of p-ERK were not significantly affected. TCA 10 μg/ml significantly decreased expression levels of MMP-1, MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5. In vivo results showed that TCA alleviated cartilage destruction and the OARSI scores. Conclusion. TCA possesses anti-inflammatory effect in vitro and exerts chondrocyte protective effects in vivo, in which NF-κB and p38-JNK were involved.

scholarly journals Monocrotaline Suppresses RANKL-Induced Osteoclastogenesis In Vitro and Prevents LPS-Induced Bone Loss In Vivo

2018 ◽  
Vol 48 (2) ◽  
pp. 644-656 ◽  
Author(s):  
Cheng-Ming Wei ◽  
Yi-Ji Su ◽  
Xiong Qin ◽  
Jia-Xin Ding ◽  
Qian Liu ◽  
...  
Keyword(s):  
Critical Role ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Bone Diseases ◽  
Marker Genes ◽  
Tartrate Resistant Acid Phosphatase ◽  
Dependent Manner ◽  
And Function

Background/Aims: Extensive osteoclast formation plays a critical role in bone diseases, including rheumatoid arthritis, periodontitis and the aseptic loosening of orthopedic implants. Thus, identification of agents that can suppress osteoclast formation and bone resorption is important for the treatment of these diseases. Monocrotaline (Mon), the major bioactive component of crotalaria sessiliflora has been investigated for its anti-cancer activities. However, the effect of Mon on osteoclast formation and osteolysis is not known. Methods: The bone marrow macrophages (BMMs) were cultured with M-CSF and RANKL followed by Mon treatment. Then the effects of Mon on osteoclast differentiation were evaluated by counting TRAP (+) multinucleated cells. Moreover, effects of Mon on hydroxyapatite resorption activity of mature osteoclast were studied through resorption areas measurement. The involved potential signaling pathways were analyzed by performed Western blotting and quantitative real-time PCR examination. Further, we established a mouse calvarial osteolysis model to measure the osteolysis suppressing effect of Mon in vivo. Results: In this study, we show that Mon can inhibit RANKL-induced osteoclast formation and function in a dose-dependent manner. Mon inhibits the expression of osteoclast marker genes such as tartrate-resistant acid phosphatase (TRAP) and cathepsin K. Furthermore, Mon inhibits RANKL-induced the activation of p38 and JNK. Consistent with in vitro results, Mon exhibits protective effects in an in vivo mouse model of LPS-induced calvarial osteolysis. Conclusion: Taken together our data demonstrate that Mon may be a potential prophylactic anti-osteoclastic agent for the treatment of osteolytic diseases caused by excessive osteoclast formation and function.

Sign in / Sign up

Export Citation Format

Share Document