scholarly journals Gasdermin D deficiency attenuates arthritis induced by traumatic injury but not autoantibody-assembled immune complexes

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Tong Yang ◽  
Kai Sun ◽  
Chun Wang ◽  
Gaurav Swarnkar ◽  
Songtao Quan ◽  
...  
Keyword(s):  
Subchondral Bone ◽  
Immune Complexes ◽  
Protein Complexes ◽  
Plate Thickness ◽  
Traumatic Injury ◽  
Cartilage Degradation ◽  
Mouse Serum ◽  
Micro Computed Tomography ◽  
Amino Terminal ◽  
Caspase 1

Abstract Background Gasdermin D (GSDMD) is cleaved by several proteases including by caspase-1, a component of intracellular protein complexes called inflammasomes. Caspase-1 also converts pro-interleukin-1β (pro-IL-1β) and pro-IL-18 into bioactive IL-1β and IL-18, respectively. GSDMD amino-terminal fragments form plasma membrane pores, which mediate the secretion of IL-1β and IL-18 and cause the inflammatory form of cell death pyroptosis. Here, we tested the hypothesis that GSDMD contributes to joint degeneration in the K/BxN serum transfer-induced arthritis (STIA) model in which autoantibodies against glucose-6-phosphate isomerase promote the formation of pathogenic immune complexes on the surface of myeloid cells, which highly express the inflammasomes. The unexpected outcomes with the STIA model prompted us to determine the role of GSDMD in the post-traumatic osteoarthritis (PTOA) model caused by meniscus ligamentous injury (MLI) based on the hypothesis that this pore-forming protein is activated by signals released from damaged joint tissues. Methods Gsdmd+/+ and Gsdmd−/− mice were injected with K/BxN mouse serum or subjected to MLI to cause STIA or PTOA, respectively. Paw and ankle swelling and DXA scanning were used to assess the outcomes in the STIA model whereas histopathology and micro-computed tomography (μCT) were utilized to monitor joints in the PTOA model. Murine and human joint tissues were also examined for GSDMD, IL-1β, and IL-18 expression by qPCR, immunohistochemistry, or immunoblotting. Results GSDMD levels were higher in serum-inoculated paws compared to PBS-injected paws. Unexpectedly, ablation of GSDMD failed to reduce joint swelling and osteolysis, suggesting that GSDMD was dispensable for the pathogenesis of STIA. GSDMD levels were also higher in MLI compared to sham-operated joints. Importantly, ablation of GSDMD attenuated MLI-associated cartilage degradation (p = 0.0097), synovitis (p = 0.014), subchondral bone sclerosis (p = 0.0006), and subchondral bone plate thickness (p = 0.0174) based on histopathological and μCT analyses. Conclusion GSDMD plays a key role in the pathogenesis of PTOA, but not STIA, suggesting that its actions in experimental arthropathy are tissue context-specific.

scholarly journals Micro-Computed Tomography Analysis of Subchondral Bone Regeneration Using Osteochondral Scaffolds in an Ovine Condyle Model

2021 ◽  
Vol 11 (3) ◽  
pp. 891
Author(s):  
Taylor Flaherty ◽  
Maryam Tamaddon ◽  
Chaozong Liu
Keyword(s):  
Computed Tomography ◽  
Bone Regeneration ◽  
Subchondral Bone ◽  
Volume Ratio ◽  
Bone Volume ◽  
Osteochondral Defects ◽  
Micro Ct ◽  
Micro Computed Tomography ◽  
Trabecular Thickness ◽  
Osteochondral Scaffold

Osteochondral scaffold technology has emerged as a promising therapy for repairing osteochondral defects. Recent research suggests that seeding osteochondral scaffolds with bone marrow concentrate (BMC) may enhance tissue regeneration. To examine this hypothesis, this study examined subchondral bone regeneration in scaffolds with and without BMC. Ovine stifle condyle models were used for the in vivo study. Two scaffold systems (8 mm diameter and 10 mm thick) with and without BMC were implanted into the femoral condyle, and the tissues were retrieved after six months. The retrieved femoral condyles (with scaffold in) were examined using micro-computed tomography scans (micro-CT), and the micro-CT data were further analysed by ImageJ with respect to trabecular thickness, bone volume to total volume ratio (BV/TV) ratio, and degree of anisotropy of bone. Statistical analysis compared bone regeneration between scaffold groups and sub-set regions. These results were mostly insignificant (p < 0.05), with the exception of bone volume to total volume ratio when comparing scaffold composition and sub-set region. Additional trends in the data were observed. These results suggest that the scaffold composition and addition of BMC did not significantly affect bone regeneration in osteochondral defects after six months. However, this research provides data which may guide the development of future treatments.

scholarly journals SOST Deficiency Aggravates Osteoarthritis in Mice by Promoting Sclerosis of Subchondral Bone

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Jingyu Li ◽  
Junjie Xue ◽  
Yan Jing ◽  
Manyi Wang ◽  
Rui Shu ◽  
...  
Keyword(s):  
Subchondral Bone ◽  
Cruciate Ligament ◽  
Cartilage Degradation ◽  
Cell Number ◽  
Blue Staining ◽  
Sham Operation ◽  
Knee Oa ◽  
Sost Gene ◽  
Bone Sclerosis ◽  
The Difference

As the initial part in the development of osteoarthritis (OA), subchondral bone sclerosis has been considered to be initiated by excess mechanical loading and proven to be correlated to other pathological changes. Sclerostin, which is an essential mechanical stress response protein, is encoded by the SOST gene. It is expressed in osteocytes and mature chondrocytes and has been proven to be closely correlated to OA. However, the relationship and mechanism between the SOST gene and the development of OA remain unclear. The aim of the present study was to investigate the role of the SOST gene in OA pathogenesis in the subchondral bone. A knee anterior cruciate ligament transection (ACLT) mouse osteoarthritis (OA) model on SOST-knockout (SOST KO) and wild-type (WT) mice was established. The pathogenic and phenotypic changes in the subchondral bone were investigated by histology, micro-CT, immunohistochemistry, TRAP staining, Masson staining, and Toluidine blue staining. It was found that sclerostin expression decreased in both the calcified cartilage and mineralized subchondral structures during the development of OA. Joint instability induced a severe cartilage degradation phenotype, with higher OARSI scores in SOST KO mice, when compared to WT mice. SOST KO mice with OA exhibited a higher BMD and BV/TV ratio, as well as a higher rate of bone remodeling and TRAP-positive cell number, when compared to the WT counterparts, but the difference was not significant between the sham-operation groups. It was concluded that loss of sclerostin aggravates knee OA in mice by promoting subchondral bone sclerosis and increasing catabolic activity of cartilage.

scholarly journals Binding of recombinant interleukin-1 beta to the third complement component and alpha 2-macroglobulin after activation of serum by immune complexes

Blood ◽  
1990 ◽  
Vol 75 (12) ◽  
pp. 2388-2395 ◽  
Author(s):  
W Borth ◽  
A Urbanski ◽  
R Prohaska ◽  
M Susanj ◽  
TA Luger
Keyword(s):  
Complex Formation ◽  
Immune Complexes ◽  
Protein Complexes ◽  
Interleukin 1 ◽  
Complement Component ◽  
Interleukin 1 Beta ◽  
Thiol Groups ◽  
Thiol Ester ◽  
The Third ◽  
Sds Page

Abstract Activation of human normal serum with tetanus/antitetanus immune complexes (TAT-IC) resulted in increased binding of 125I-labeled interleukin-1 beta (IL-1 beta) to serum factors, as opposed to untreated serum. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by autoradiography showed labeling of two large molecular mass factors of an apparent molecular weight (Mr) of 200,000 and 400,000, respectively. These complexes could be dissociated by reduction. No complexes were formed when reducing compounds were added to serum-TAT-IC-125I-IL-1 beta mixtures. Complex formation was largely prevented by alkylating compounds. Molecular sieve chromatography of TAT-IC-activated serum confirmed that 125I-IL-1 beta became bound to high Mr serum proteins. Fractions containing high molecular 125I-IL-1 serum protein complexes partially retained IL-1- like activity since they induced proliferation of an IL-1-dependent murine T helper (D10G4) cell lineage. The 125I-IL-1 beta binding factors could be immunoprecipitated from TAT-IC-activated serum 125I-IL- 1 beta solutions by antisera to alpha 2-macroglobulin (alpha 2M) or to the third complement component (C3). SDS-PAGE of the immunoprecipitates showed radioactive bands corresponding to the expected Mr resulting from complex formation between 125I-IL-1 beta and these two proteins. Treatment of purified plasma alpha 2M and C3 with trypsin or activation with methylamine, which causes cleavage of the internal thiol ester and the appearance of free thiol groups in these proteins, mediated binding of 125I-IL-1 beta to alpha 2M and C3b. The results suggest that cleavage of the internal thiol ester in C3 and alpha 2M makes these plasma proteins susceptible to binding of 125I-IL-1 beta and that free thiol groups do play a role in the formation of 125I-IL-1 beta plasma protein complexes. Activated C3 and alpha 2M may function as IL-1 beta carrier proteins in biologic fluids, in addition to their other physiologic roles.

scholarly journals Attenuation of Trauma-induced Osteoarthritis by Repetitive Intra-articular Administration of Peripheral Blood Derived Mesenchymal Stem Cells

2021 ◽  
Author(s):  
Weiping Lin ◽  
Zhengmeng Yang ◽  
Liu Shi ◽  
Haixing Wang ◽  
Qi Pan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Articular Cartilage ◽  
Subchondral Bone ◽  
Peripheral Blood ◽  
Cartilage Degradation ◽  
Cartilage Tissue ◽  
Synovial Joint ◽  
Post Surgery ◽  
Sham Surgery

Abstract Background: Osteoarthritis (OA) is a chronic joint disease, characterized by articular cartilage degradation, subchondral bone hardening, and inflammation of the whole synovial joint. There is no pharmacological treatment in slowing down OA progression, leading to costly surgical interventions eventually. Cell therapy using chondrocytes or progenitor cells from different sources has been reported in clinical trials for OA management with some success, but outcomes are varied. Peripheral blood derived mesenchymal stem cells (PB-MSCs) are promising cells owing to their easy collection, superior migration, and differentiation potentials. In the current study, we evaluated the effect of intra-articular administration of PB-MSCs on the progression of OA in mice.Methods: C57BL/6J mice (8-10 weeks old male) were subjected to destabilization of the medial meniscus surgeries (DMM) on their right joints following protocols as previously reported. The mice after DMM were randomly treated with saline (vehicle control), PB-MSCs, or adipose tissue derived MSCs (AD-MSCs) (n = 7 per group). The mice treated with sham surgery were regarded as sham controls (n = 7). PB-MSCs and AD-MSCs were harvested and cultured according to previous published protocols, and pre-labeled with BrdU for 48 h before use. PB-MSCs or AD-MSCs (5 × 105 cells/mouse; passage 3~5) were injected into the right knee joints thrice post-surgery (except sham surgery group). The mice were euthanized at 8 weeks post-surgery and knee joint samples were collected for micro-CT and histological examinations.Results: PB-MSCs administration significantly reduced hardening of subchondral bone comparing to vehicle controls. Safranin O staining showed that PB-MSCs treatment ameliorated degeneration of articular cartilage, which is comparable to AD-MSCs treatment. The expression of catabolic marker MMP13 was significantly reduced in articular cartilage of PB-MSCs-treated groups comparing to vehicle controls. Co-expression of BrdU and Sox9 were detected, indicating injected PB-MSCs differentiated towards chondrocytes in situ. Reduced level of IL-6 in the peripheral sera of PB-MSCs- and AD-MSCs-treated mice was also determined. Conclusions: Repetitive administration of PB-MSCs or AD-MSCs halted OA progression through inhibiting cartilage degradation and inflammation. PB-MSCs may become a promising cell source for cartilage tissue repair and alleviation of OA progression.

scholarly journals Noggin Inhibits IL-1β and BMP-2 Expression, and Attenuates Cartilage Degeneration and Subchondral Bone Destruction in Experimental Osteoarthritis

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 927 ◽  
Author(s):  
Szu-Yu Chien ◽  
Chun-Hao Tsai ◽  
Shan-Chi Liu ◽  
Chien-Chung Huang ◽  
Tzu-Hung Lin ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Signaling Pathways ◽  
Bone Remodeling ◽  
Subchondral Bone ◽  
Bone Destruction ◽  
Cartilage Degeneration ◽  
Cartilage Degradation ◽  
Mitogen Activated Protein Kinase ◽  
Bone Morphogenetic Protein 2 ◽  
Joint Disease

Osteoarthritis (OA) is a chronic inflammatory and progressive joint disease that results in cartilage degradation and subchondral bone remodeling. The proinflammatory cytokine interleukin 1 beta (IL-1β) is abundantly expressed in OA and plays a crucial role in cartilage remodeling, although its role in the activity of chondrocytes in cartilage and subchondral remodeling remains unclear. In this study, stimulating chondrogenic ATDC5 cells with IL-1β increased the levels of bone morphogenetic protein 2 (BMP-2), promoted articular cartilage degradation, and enhanced structural remodeling. Immunohistochemistry staining and microcomputed tomography imaging of the subchondral trabecular bone region in the experimental OA rat model revealed that the OA disease promotes levels of IL-1β, BMP-2, and matrix metalloproteinase 13 (MMP-13) expression in the articular cartilage and enhances subchondral bone remodeling. The intra-articular injection of Noggin protein (a BMP-2 inhibitor) attenuated subchondral bone remodeling and disease progression in OA rats. We also found that IL-1β increased BMP-2 expression by activating the mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase (ERK), and specificity protein 1 (Sp1) signaling pathways. We conclude that IL-1β promotes BMP-2 expression in chondrocytes via the MEK/ERK/Sp1 signaling pathways. The administration of Noggin protein reduces the expression of IL-1β and BMP-2, which prevents cartilage degeneration and OA development.

scholarly journals Functional degradation: A mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes

Science ◽  
2019 ◽  
Vol 364 (6435) ◽  
pp. eaau1330 ◽  
Author(s):  
Andrew Sandstrom ◽  
Patrick S. Mitchell ◽  
Lisa Goers ◽  
Edward W. Mu ◽  
Cammie F. Lesser ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Ubiquitin Ligase ◽  
Shigella Flexneri ◽  
Inflammasome Activation ◽  
Anthrax Lethal Toxin ◽  
Degradation Model ◽  
Amino Terminal ◽  
Caspase 1 ◽  
Carboxyl Terminal ◽  
Necessary And Sufficient

Inflammasomes are multiprotein platforms that initiate innate immunity by recruitment and activation of caspase-1. The NLRP1B inflammasome is activated upon direct cleavage by the anthrax lethal toxin protease. However, the mechanism by which cleavage results in NLRP1B activation is unknown. In this study, we find that cleavage results in proteasome-mediated degradation of the amino-terminal domains of NLRP1B, liberating a carboxyl-terminal fragment that is a potent caspase-1 activator. Proteasome-mediated degradation of NLRP1B is both necessary and sufficient for NLRP1B activation. Consistent with our functional degradation model, we identify IpaH7.8, aShigella flexneriubiquitin ligase secreted effector, as an enzyme that induces NLRP1B degradation and activation. Our results provide a unified mechanism for NLRP1B activation by diverse pathogen-encoded enzymatic activities.

scholarly journals Noncoding RNAs in subchondral bone osteoclast function and their therapeutic potential for osteoarthritis

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Li Duan ◽  
Yujie Liang ◽  
Xiao Xu ◽  
Jifeng Wang ◽  
Xingfu Li ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Remodeling ◽  
Subchondral Bone ◽  
Therapeutic Potential ◽  
Osteoclast Differentiation ◽  
Noncoding Rnas ◽  
Cartilage Degradation ◽  
Joint Disease ◽  
Molecular Signaling ◽  
Osteoclast Function

AbstractOsteoclasts are the only cells that perform bone resorption. Noncoding RNAs (ncRNAs) are crucial epigenetic regulators of osteoclast biological behaviors ranging from osteoclast differentiation to bone resorption. The main ncRNAs, including miRNAs, circRNAs, and lncRNAs, compose an intricate network that influences gene transcription processes related to osteoclast biological activity. Accumulating evidence suggests that abnormal osteoclast activity leads to the disturbance of subchondral bone remodeling, thus initiating osteoarthritis (OA), a prevalent joint disease characterized mainly by cartilage degradation and subchondral bone remodeling imbalance. In this review, we delineate three types of ncRNAs and discuss their related complex molecular signaling pathways associated with osteoclast function during bone resorption. We specifically focused on the involvement of noncoding RNAs in subchondral bone remodeling, which participate in the degradation of the osteochondral unit during OA progression. We also discussed exosomes as ncRNA carriers during the bone remodeling process. A better understanding of the roles of ncRNAs in osteoclast biological behaviors will contribute to the treatment of bone resorption-related skeletal diseases such as OA.

scholarly journals DEVELOPING THE COMMON MARMOSET AS A TRANSLATIONAL MODEL OF AGE-RELATED OSTEOARTHRITIS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S104-S104
Author(s):  
Dennis M Minton ◽  
Angela J Marolf ◽  
Kelly S Santangelo ◽  
Adam B Salmon ◽  
Adam R Konopka
Keyword(s):  
Subchondral Bone ◽  
Bone Structure ◽  
Common Marmoset ◽  
Knee Joints ◽  
Micro Computed Tomography ◽  
Bone Thickness ◽  
Aging Research ◽  
Naturally Occurring ◽  
Age Related ◽  
The Common

Abstract Age is a primary risk factor for osteoarthritis (OA). The mechanisms that contribute to OA are poorly understood and disease modifying treatments have not been identified. A critical shortcoming in developing therapies is the limited number of translational models available to identify the causes of naturally occurring OA. Our goal is to use the common marmoset as a non-human primate (NHP) model of age-related OA. NHP are the closest evolutionary relative to humans and share many characteristics of human aging. The marmoset has advantages over other NHP for aging research because of their relatively short maximal lifespan and small size. Micro-computed tomography (uCT) was performed on whole-knee joints obtained from young (10 yrs, n=3) marmosets at necropsy. OA was evaluated using a clinical uCT scoring system and quantitative assessments of subchondral bone structure and ossified meniscal volume. Advancing age was positively correlated to increased uCT OA score (p&lt;0.05, r=0.59 ), mainly through increased number and size of osteophytes and progressive subchondral bone sclerosis from the medial to both medial and lateral compartments. For marmosets displaying meniscal ossification, older marmosets had greater (p&lt;0.05) ossified meniscal volume than middle-aged and younger marmosets, respectively. Trabecular (p=0.05) and cortical bone thickness (p&lt;0.05) were also lower in older marmosets. These data are the first to indicate that the marmoset develops naturally occurring, age-related OA and support the pursuit of additional studies using the marmoset to identify OA mechanisms and test potential interventions.

Sign in / Sign up

Export Citation Format

Share Document