Fcgr2b and Fcgr3 are the major genetic factors for cartilage antibody-induced arthritis, overriding the effect of Hc encoding complement C5.

Like rheumatoid arthritis (RA) in humans, collagen-induced arthritis (CIA) in mice is associated with not only MHC class II genetic polymorphism but also, to some extent, with other loci including genes encoding Fc gamma receptors (FCGRs) and complement C5. In this study, we used a cartilage antibody-induced arthritis (CAIA) model in which arthritis develops within a 12-h timeframe, to determine the relative importance of FCGRs and C5 (Hc). In CAIA, inhibiting or deleting FCGR3 substantially hindered arthritis development, underscoring the crucial role of this receptor. Blocking FCGR3 also reduced the levels of FCGR4, and vice versa. When employing an IgG1 arthritogenic cocktail that exclusively interacts with FCGR2B and FCGR3, joint inflammation was promptly initiated in Fcgr2b-- mice but not in Fcgr3-- mice, suggesting that FCGR3 is sufficient for CAIA development. Regarding complement activation, Fcgr2b++.Hc** mice with C5 mutated were fully resistant to CAIA, whereas Fcgr2b--.Hc** mice developed arthritis rapidly. We conclude that FCGR3 is essential and sufficient for CAIA development, particularly when induced by IgG1 antibodies. The human ortholog of mouse FCGR3, FCGR2A, may be associated with RA pathogenesis. FCGR2B deficiency allows for rapid arthritis progression and overrides the resistance conferred by C5 deficiency.

The Combined Intraosseous Administration of Orthobiologics Outperformed Isolated Intra-articular Injections in Alleviating Pain and Cartilage Degeneration in a Rat Model of MIA-Induced Knee Osteoarthritis.

BACKGROUND: Intra-articular (IA) platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC) injections have shown efficacy and safety in treating osteoarthritis (OA). However, the effectiveness and mechanisms of combined intraosseous (IO) administration of these orthobiologics have yet to be explored. PURPOSE/HYPOTHESIS: The purpose of this study was to evaluate the effect on pain, cartilage, synovium/infrapatellar fat pad (IFP), and subchondral bone in rat knee OA, comparing isolated IA with combined IA and IO (IA+IO) injections of PRP or BMAC. It was hypothesized that combined injections would be superior to sole IA injections. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 48 rats were divided into 6 groups: sham (only joint puncture during OA induction with IA+IO saline injection treatment) and 5 groups with OA induction, control (IA+IO saline injection), PRP (IA PRP+IO saline injection), BMAC IA (IA BMAC+IO saline injection), PRP IA+IO (IA+IO PRP injection), and BMAC IA+IO (IA+IO BMAC injection). OA was induced by IA injection of monosodium iodoacetate (MIA). Rats were administered different orthobiologics according to their grouping 3 weeks after the MIA injection. Pain changes were evaluated using the weightbearing ratio assay at weeks 3, 4, 5, 7, and 9 after OA induction. Rats were euthanized at week 9 for gross, radiological, histological, immunohistochemical, and immunofluorescence assessments of cartilage, synovium, and subchondral bone. RESULTS: Compared with the control group, all orthobiologics injection groups had reduced joint pain. Compared with IA injection, IA+IO injections provided superior pain relief by suppressing calcitonin gene-related peptide and substance P in both the synovium/IFP and subchondral bone. IA+IO injections slowed the progression of subchondral bone lesions by inhibiting CD31hiEmcnhi vessel formation and excessive osteoclast and osteoblast turnover while preserving subchondral bone microarchitecture, slowing cartilage degeneration. However, IA+IO injections did not outperform isolated IA injections in reducing synovitis and synovium/IFP fibrosis. Compared with PRP, BMAC exhibited superior inhibition of pain-related mediators, but no significant differences were observed in synovitis suppression, infrapatellar fat pad fibrosis, and subchondral bone protection. CONCLUSION: IA+IO injections of orthobiologics were more effective in relieving pain, slowing cartilage degeneration, and inhibiting abnormal vascularization and remodeling compared with isolated IA injections. BMAC showed superior pain relief in the synovium/IFP and subchondral bone compared with PRP. Further research is needed to optimize PRP and BMAC components for enhanced efficacy in OA management. CLINICAL RELEVANCE: Our findings contribute to advancing the understanding of pain relief mechanisms and support the endorsement of IO injection of orthobiologics for the treatment of OA and joint pain.

Cartilage destruction in early rheumatoid arthritis patients correlates with CD21-/low double-negative B cells.

BACKGROUND: Involvement of B cells in the pathogenesis of rheumatoid arthritis (RA) is supported by the presence of disease-specific autoantibodies and the efficacy of treatment directed against B cells. B cells that express low levels of or lack the B cell receptor (BCR) co-receptor CD21, CD21-/low B cells, have been linked to autoimmune diseases, including RA. In this study, we characterized the CD21+ and CD21-/low B cell subsets in newly diagnosed, early RA (eRA) patients and investigated whether any of the B cell subsets were associated with autoantibody status, disease activity and/or joint destruction. METHODS: Seventy-six eRA patients and 28 age- and sex-matched healthy donors were recruited. Multiple clinical parameters were assessed, including disease activity and radiographic joint destruction. B cell subsets were analysed in peripheral blood (PB) and synovial fluid (SF) using flow cytometry. RESULTS: Compared to healthy donors, the eRA patients displayed an elevated frequency of naïve CD21+ B cells in PB. Amongst memory B cells, eRA patients had lower frequencies of the CD21+CD27+ subsets and CD21-/low CD27+IgD+ subset. The only B cell subset found to associate with clinical factors was the CD21-/low double-negative (DN, CD27-IgD-) cell population, linked with the joint space narrowing score, i.e. cartilage destruction. Moreover, in SF from patients with established RA, the CD21-/low DN B cells were expanded and these cells expressed receptor activator of the nuclear factor κB ligand (RANKL). CONCLUSIONS: Cartilage destruction in eRA patients was associated with an expanded proportion of CD21-/low DN B cells in PB. The subset was also expanded in SF from established RA patients and expressed RANKL. Taken together, our results suggest a role for CD21-/low DN in RA pathogenesis.

Exploring molecular mechanisms of intra-articular changes in osteonecrosis of femoral head using DIA proteomics and bioinformatics.

PURPOSE: This study is aimed to delve into the crucial proteins associated with hormonal osteonecrosis of the femoral head (ONFH) and its intra-articular lesions through data-independent acquisition (DIA) proteomics and bioinformatics analysis. METHODS: We randomly selected samples from eligible ONFH patients and collected samples from the necrotic area of the femoral head and load-bearing cartilage. The control group comprised specimens from the same location in patients with femoral neck fractures. With DIA proteomics, we quantitatively and qualitatively tested both groups and analyzed the differentially expressed proteins (DEPs) between groups. Additionally, we enriched the analysis of DEP functions using gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways and verified the key proteins in ONFH through Western blot. RESULTS: Proteomics experiment uncovered 937 common DEPs (422 upregulated and 515 downregulated) between the two groups. These DEPs mainly participate in biological processes such as hidden attributes, catalytic activity, molecular function regulators, and structural molecule activity, and in pathways such as starch and sucrose metabolism, ECM-receptor interaction, PI3K-Akt signaling, complement and coagulation cascades, IL-17 signaling, phagosome, transcriptional misregulation in cancers, and focal adhesion. Through protein-protein interaction network target gene analysis and Western blot validation, we identified C3, MMP9, APOE, MPO, LCN2, ELANE, HPX, LTF, and THBS1 as key proteins in ONFH. CONCLUSIONS: With DIA proteomics and bioinformatics analysis, this study reveals the molecular mechanisms of intra-articular lesions in ONFH. A correlation in the necrotic area and load-bearing cartilage of ONFH at ARCO stages IIIB-IV as well as potential key regulatory proteins was identified. These findings will help more deeply understand the pathogenesis of ONFH and may provide important clues for seeking more effective treatment strategies.

TLR4 antagonism provides short-term but not long-term clinical benefit in a full-depth cartilage defect mouse model.

PURPOSE/AIM: Cartilage injury and subsequent osteoarthritis (OA) are debilitating conditions affecting millions worldwide. As there are no cures for these ailments, novel therapies are needed to suppress disease pathogenesis. Given that joint injuries are known to produce damage-associated molecular patterns (DAMPs), our central premise is that the Toll-like receptor 4 (TLR4) pathway is a principal driver in the early response to cartilage damage and subsequent pathology. We postulate that TLR4 activation is initiated/perpetuated by DAMPs released following joint damage. Thus, antagonism of the TLR4 pathway immediately after injury may suppress the development of joint surface defects. MATERIALS AND METHODS: Two groups were utilized: (1) 8-week-old, male C57BL6 mice treated systemically with a known TLR4 antagonist and (2) mice injected with vehicle control. A full-depth cartilage lesion on the midline of the patellofemoral groove was created in the right knee of each mouse. The left knee was used as a sham surgery control. Gait changes were evaluated over 4 weeks using a quantitative gait analysis system. At harvest, knee joints were processed for pathologic assessment, Nanostring® transcript expression, and immunohistochemistry (IHC). RESULTS: Short-term treatment with a TLR4 antagonist at 14-days significantly improved relevant gait parameters; improved cartilage metrics and modified Mankin scores were also seen. Additionally, mRNA expression and IHC showed reduced expression of inflammatory mediators in animals treated with the TLR4 antagonist. CONCLUSIONS: Collectively, this work demonstrates that systemic treatment with a TLR4 antagonist is protective to further cartilage damage 14-days post-injury in a murine model of induced disease.

Association between knee magnetic resonance imaging markers and knee symptoms over 6-9 years in young adults.

OBJECTIVES: To describe associations between MRI markers with knee symptoms in young adults. METHODS: Knee symptoms were assessed using the WOMAC scale during the Childhood Determinants of Adult Health Knee Cartilage study (CDAH-knee; 2008-2010) and at the 6- to 9-year follow-up (CDAH-3; 2014-2019). Knee MRI scans obtained at baseline were assessed for morphological markers (cartilage volume, cartilage thickness, subchondral bone area) and structural abnormalities [cartilage defects and bone marrow lesions (BMLs)]. Univariable and multivariable (age, sex, BMI adjusted) zero-inflated Poisson (ZIP) regression models were used for analysis. RESULTS: The participants' mean age in CDAH-knee and CDAH-3 were 34.95 (s.d. 2.72) and 43.27 (s.d. 3.28) years, with 49% and 48% females, respectively. Cross-sectionally, there was a weak but significant negative association between medial femorotibial compartment (MFTC) [ratio of the mean (RoM) 0.99971084 (95% CI 0.9995525, 0.99986921), P < 0.001], lateral femorotibial compartment (LFTC) [RoM 0.99982602 (95% CI 0.99969915, 0.9999529), P = 0.007] and patellar cartilage volume [RoM 0.99981722 (95% CI 0.99965326, 0.9999811), P = 0.029] with knee symptoms. Similarly, there was a negative association between patellar cartilage volume [RoM 0.99975523 (95% CI 0.99961427, 0.99989621), P = 0.014], MFTC cartilage thickness [RoM 0.72090775 (95% CI 0.59481806, 0.87372596), P = 0.001] and knee symptoms assessed after 6-9 years. The total bone area was negatively associated with knee symptoms at baseline [RoM 0.9210485 (95% CI 0.8939677, 0.9489496), P < 0.001] and 6-9 years [RoM 0.9588811 (95% CI 0.9313379, 0.9872388), P = 0.005]. The cartilage defects and BMLs were associated with greater knee symptoms at baseline and 6-9 years. CONCLUSION: BMLs and cartilage defects were positively associated with knee symptoms, whereas cartilage volume and thickness at MFTC and total bone area were weakly and negatively associated with knee symptoms. These results suggest that the quantitative and semiquantitative MRI markers can be explored as a marker of clinical progression of OA in young adults.

Mechanical loading of joint modulates T cells in lymph nodes to regulate osteoarthritis.

OBJECTIVE: The crosstalk of joint pathology with local lymph nodes in osteoarthritis (OA) is poorly understood. We characterized the change in T cells in lymph nodes following load-induced OA and established the association of the presence and migration of T cells to the onset and progression of OA. METHODS: We used an in vivo model of OA to induce mechanical load-induced joint damage. After cyclic tibial compression of mice, we analyzed lymph nodes for T cells using flow cytometry and joint pathology using histology and microcomputed tomography. The role of T-cell migration and the presence of T-cell type was examined using T-cell receptor (TCR)α-/- mice and an immunomodulatory drug, Sphingosine-1-phosphate (S1P) receptor inhibitor-treated mice, respectively. RESULTS: We demonstrated a significant increase in T-cell populations in local lymph nodes in response to joint injury in 10, 16, and 26-week-old mice, and as a function of load duration, 1, 2, and 6 weeks. T-cell expression of inflammatory cytokine markers increased in the local lymph nodes and was associated with load-induced OA progression in the mouse knee. Joint loading in TCRα-/- mice reduced both cartilage degeneration (Osteoarthritis Research Society International (OARSI) scores: TCRα 0.568, 0.981-0.329 confidence interval (CI); wild type (WT) 1.328, 2.353-0.749 CI) and osteophyte formation. Inhibition of T-cell egress from lymph nodes attenuated load-induced cartilage degradation (OARSI scores: Fingolimod: 0.509, 1.821-0.142 CI; Saline 1.210, 1.932-0.758 CI) and decreased localization of T cells in the synovium. CONCLUSIONS: These results establish the association of lymph node-resident T cells in joint damage and suggest that the S1P receptor modulators and T-cell immunotherapies could be used to treat OA.

Sonographic Findings of Cervical Chondrocutaneous Branchial Remnants-A Comparison With Dermal Lesions/Cysts and a Literature Review: A Pilot Study.

OBJECTIVES: Cervical chondrocutaneous branchial remnants (CCBRs) and dermal lesions, such as epidermoid cysts or brachial anomalies, including lateral cervical cysts/sinuses or dermal sinuses of anterior chest lesions, are usually located at the lower neck at the anterior or posterior border of the sternocleidomastoid muscle (SCM). We aimed to demonstrate the usefulness of ultrasonography in the differential diagnosis and evaluation of CCBRs. METHODS: We evaluated 22 lesions of 20 pediatric patients, classified into CCBR and dermal lesion groups. We used Fisher's exact test to evaluate differences between these groups in terms of lesion shape (low-echoic mass- or tubular-like), whether the lesion was adjacent to/in contact with the SCM or not, and the presence or absence of a concave SCM caused by the lesion. RESULTS: Of the 22 lesions, 8 were CCBRs, and 14 were dermal lesions. We found a significant difference in the presence/absence of adjacency to or contact with the SCM (presence/absence of adjacency to or contact with the SCM in CCBRs vs that in dermal lesions: 6/2 vs 1/13, P = .002) and presence/absence of lesion-induced concavity of the SCM (presence/absence of lesion-induced concavity of the SCM in CCBRs vs that in dermal lesions: 3/5 vs 0/14, P = .036). The lesion shape (low-echoic mass-like/tubular-like lesions) did not significantly differ between the two study groups (low-echoic mass-like/tubular-like lesions in CCBRs vs that in dermal lesions: 5/3 vs 11/6, P = .624). CONCLUSIONS: CCBRs have a strong association with the SCM. These sonographic findings may be useful in the differential diagnosis of dermal cervical lesions.

Ruscogenin attenuates cartilage destruction in osteoarthritis through suppressing chondrocyte ferroptosis via Nrf2/SLC7A11/GPX4 signaling pathway.

Osteoarthritis (OA) is a common joint degenerative disease, and chondrocyte injury is the main pathological and physiological change. Ruscogenin (Rus), a bioactive compound isolated from Radix Ophiopogon japonicus, exhibits various pharmacological effects. The aim of this research was to test the role and mechanism of Rus on OA both in vivo and in vitro. Destabilized medial meniscus (DMM)-induced OA model was established in vivo and IL-1ß-stimulated mouse chondrocytes was used to explore the role of Rus on OA in vitro. In vivo, Rus exhibited protective effects against DMM-induced OA model. Rus could inhibit MMP1 and MMP3 expression in OA mice. In vitro, IL-1ß-induced inflammation and degradation of extracellular matrix were inhibited by Rus, as confirmed by the inhibition of PGE2, NO, MMP1, and MMP3 by Rus. Also, IL-1ß-induced ferroptosis was suppressed by Rus, as confirmed by the inhibition of MDA, iron, and ROS, as well as the upregulation of GSH, GPX4, Ferritin, Nrf2, and SLC7A11 expression induced by Rus. Furthermore, the suppression of Rus on IL-1ß-induced inflammation, MMPs production, and ferroptosis were reversed when Nrf2 was knockdown. In conclusion, Rus attenuated OA progression through inhibiting chondrocyte ferroptosis via Nrf2/SLC7A11/GPX4 signaling pathway.

Aberrant Activation of Immune and Non-Immune Cells Contributes to Joint Inflammation and Bone Degradation in Rheumatoid Arthritis.

Abnormal activation of multiple immune and non-immune cells and proinflammatory factors mediate the development of joint inflammation in genetically susceptible individuals. Although specific environmental factors like smoking and infections are associated with disease pathogenesis, until now, we did not know the autoantigens and arthritogenic factors that trigger the initiation of the clinical disease. Autoantibodies recognizing specific post-translationally modified and unmodified antigens are generated and in circulation before the onset of the joint disease, and could serve as diagnostic and prognostic markers. The characteristic features of autoantibodies change regarding sub-class, affinity, glycosylation pattern, and epitope spreading before the disease onset. Some of these antibodies were proven to be pathogenic using animal and cell-culture models. However, not all of them can induce disease in animals. This review discusses the aberrant activation of major immune and non-immune cells contributing to joint inflammation. Recent studies explored the protective effects of extracellular vesicles from mesenchymal stem cells and bacteria on joints by targeting specific cells and pathways. Current therapeutics in clinics target cells and inflammatory pathways to attenuate joint inflammation and protect the cartilage and bones from degradation, but none cure the disease. Hence, more basic research is needed to investigate the triggers and mechanisms involved in initiating the disease and relapses to prevent chronic inflammation from damaging joint architecture.

Exosome-Laden Scaffolds for Treatment of Post-Traumatic Cartilage Injury and Osteoarthritis of the Knee: A Systematic Review.

Mesenchymal stem cell (MSC)-based exosomes have garnered attention as a viable therapeutic for post-traumatic cartilage injury and osteoarthritis of the knee; however, efforts for application have been limited due to issues with variable dosing and rapid clearance in vivo. Scaffolds laden with MSC-based exosomes have recently been investigated as a solution to these issues. Here, we review in vivo studies and highlight key strengths and potential clinical uses of exosome-scaffold therapeutics for treatment of post-traumatic cartilage injury and osteoarthritis. In vivo animal studies were gathered using keywords related to the topic, revealing 466 studies after removal of duplicate papers. Inclusion and exclusion criteria were applied for abstract screening and full-text review. Thirteen relevant studies were identified for analysis and extraction. Three predominant scaffold subtypes were identified: hydrogels, acellular extracellular matrices, and hyaluronic acid. Each scaffold-exosome design showcased unique properties with relation to gross findings, tissue histology, biomechanics, and gene expression. All designs demonstrated a reduction in inflammation and induction of tissue regeneration. The results of our review show that current exosome-scaffold therapeutics demonstrate the capability to halt and even reverse the course of post-traumatic cartilage injury and osteoarthritis. While this treatment modality shows incredible promise, future research should aim to characterize long-term biocompatibility and optimize scaffold designs for human treatment.

[Research progress in the pathologic mechanism of temporomandibular joint osteoarthritis].

Temporomandibular joint osteoarthritis (TMJOA) is a kind of degenerative lesion in temporomandibular joint disorders. The pathogenesis of TMJOA is complex. Among them, excessive mechanical stress plays an important role, which can cause a series of pathological changes, including synovial inflammation, chondrocyte death, osteogenic and adipogenic differentiation, degradation of extracellular matrix of cartilage, angiogenesis, osteochondral interface sclerosis, subchondral bone remodeling, degeneration of articular discs, etc. In the pathogenesis of TMJOA, it involves multiple signal pathways and epigenetic regulation, which may become potential therapeutic targets of TMJOA. In this paper, the research progress on the pathologic mechanism of TMJOA in recent years is reviewed to provide a basis for finding new therapeutic targets of TMJOA.

Cartilage and bone loss in premenopausal women with rheumatoid arthritis: Radiological and laboratory assessments.

INTRODUCTION: To investigate the radiological and laboratory features of bone and cartilage losses in premenopausal women with rheumatoid arthritis (RA). METHODS: This case-control study is the continuation of a study that was conducted on 48 women with RA and 48 matched healthy volunteers. All RA patients were previously subjected to clinical examination, disease activity assessment using the 28-joint Disease Activity Score (DAS28) and Clinical Disease Activity Index (CDAI), serological tests, dual-energy X-ray absorptiometry measuring bone mineral density (BMD), and plain X-ray of both hands. Added to these, matrix metalloproteinase 3 (MMP-3) and cartilage oligomeric matrix protein (COMP) were measured by enzyme-linked immunosorbent assay. RESULTS: There were statistically significant differences between patients and controls regarding COMP and MMP-3, being higher in patients (p < .001). COMP and MMP-3 have significant positive correlation with serum levels of anti-cyclic citrullinated peptide (anti-CCP) and anti-carbamylated protein (anti-CarP). The original Sharp erosion score was positively correlated with the serum level of the studied antibodies and disease duration, but no significant correlation was found with either COMP, MMP-3, or DAS-28. Spine BMD and Z score were negatively correlated with disease activity and anti-CarP. There were significant positive relationhsips between indices of local cartilage and bone loss and the indices of systemic bone loss. MMP-3 had no correlation with indices of local cartilage and bone loss and disease activity scores. CONCLUSIONS: The pathogenic mechanism of hand joint damage involved the three studied autoantibodies namely, rheumatoid factor, anti-CCP and anti-CarP antibodies. Anti-CarP antibody was involved in the reduction of BMD of the spine. The association between systemic osteoporosis and hand joint damage pointed to a common pathogenic mechanism.

Nitisinone Treatment Affects Biomarkers of Bone and Cartilage Remodelling in Alkaptonuria Patients.

Nitisinone has been approved for treatment of alkaptonuria (AKU). Non-invasive biomarkers of joint tissue remodelling could aid in understanding the molecular changes in AKU pathogenesis and how these can be affected by treatment. Serological and urinary biomarkers of type I collagen and II collagen in AKU were investigated in patients enrolled in the randomized SONIA 2 (NCT01916382) clinical study at baseline and yearly until the end of the study (Year 4). The trajectories of the biomarkers over time were observed. After treatment with nitisinone, the biomarkers of type I collagen remodelling increased at Year 1 (19% and 40% increase in CTX-I and PRO-C1, respectively), which was potentially reflected in the higher degree of mobility seen following treatment. The biomarkers of type II collagen remodelling decreased over time in the nitisinone group: C2M showed a 9.7% decline at Year 1, and levels then remained stable over the following visits; CTX-II showed a 26% decline at Year 3 and 4 in the nitisinone-treated patients. Nitisinone treatment induced changes in biomarkers of bone and cartilage remodelling. These biomarkers can aid patient management and deepen our knowledge of the molecular mechanisms of this rare disease.

The Pathogenesis of Rheumatoid Arthritis Breakthroughs in Molecular Mechanisms 1 and 2.

The pathogenesis of rheumatoid arthritis (RA) consists of the formation of synovial villi, inflammation, immune abnormalities, and bone-cartilage destruction [...].

Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) reveals potential lipid markers between infrapatellar fat pad biopsies of osteoarthritis and cartilage defect patients.

The incidence of osteoarthritis (OA) has been expected to increase due to an aging population, as well as an increased incidence of intra-articular (osteo-) chondral damage. Lipids have already been shown to be involved in the inflammatory process of OA. This study aims at revealing region-specific lipid profiles of the infrapatellar fat pad (IPFP) of OA or cartilage defect patients by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), which could be used as biomarkers for early OA detection. A higher presence of phospholipids was found in OA patients compared with cartilage defect patients. In addition, a higher abundance of ether-linked phosphatidylethanolamines (PE O-s) containing arachidonic acid was specifically found in OA patients compared with cartilage defect patients. These lipids were mainly found in the connective tissue of the IPFP. Specific lipid species were associated to OA patients compared with cartilage defect patients. PE O-s have been suggested as possible biomarkers for OA. As these were found more abundantly in the connective tissue, the IPFP's intra-tissue heterogeneity might play an important role in biomarker discovery, implying that the amount of fibrous tissue is associated with OA.

Iron regulates chondrocyte phenotype in haemophilic cartilage through the PTEN/PI3 K/AKT/FOXO1 pathway.

OBJECTIVE: Our previous study demonstrated that iron overload could lead to haemophilic cartilage destruction by changing chondrocyte phenotype. This change was caused by iron's effect on chondrocyte expression of FGF23 and SOX9, in addition to iron-induced chondrocyte apoptosis and cartilage extracellular matrix degradation. However, the underlying mechanisms remain unclear. This study aimed to determine the mechanism by which iron influences chondrocyte phenotype in the pathogenesis of haemophilic cartilage destruction. METHODS: The expression of the PTEN/PI3K/AKT/FOXO1 signal pathway in the articular cartilage of patients with haemophilic arthritis (HA) or osteoarthritis (OA) was determined using western blot (WB). Additionally, we quantified the expression of iron-induced PTEN, PI3K, p-PI3K, AKT, p-AKT, FOXO1, and p-FOXO1 in primary human normal chondrocyte cells (HUM-iCell-s018) using WB. RESULTS: We found that compared to that in patients with OA, the expression of PTEN, PI3K, AKT, and FOXO1 in the articular cartilage of patients with HA was up-regulated, while the expression of p-PI3K, p-AKT, and p-FOXO1 was down-regulated. Additionally, iron increased the expression of PTEN, PI3K, AKT, and FOXO1 and suppressed that of p-PI3K, p-AKT, and p-FOXO1 in chondrocytes in a dose-dependent manner. CONCLUSIONS: Our findings demonstrated that iron was involved in the pathogenesis of haemophilic cartilage destruction by affecting chondrocyte phenotype through the inhibition of the PTEN/PI3K/AKT/FOXO1 pathway.

Complex-Type N-Glycans Are Associated with Cartilage Degeneration within Different Loading Sites of the Tibial Plateau for Knee Osteoarthritis Patients.

Abnormal N-glycosylation has been shown to play an important role in the pathogenesis of multiple diseases. However, little is known about the relationship between N-glycosylation and knee osteoarthritis (KOA) progression at the tissue level. Thus, the aim of this study was to quantify the cartilage histomorphometric changes in formalin-fixed paraffin-embedded (FFPE) tissue collected from the lateral and medial compartments of the tibial plateau KOA patients (n = 8). Subsequently, N-glycans were analyzed by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) followed by in situ MS/MS fragmentation. Overall, the Osteoarthritis Research Society International (OARSI) histological grade and cartilage surface fibrillation index were significantly higher, and chondrocyte size in the superficial zone was much larger, for the medial high-loaded cartilage compared to the lateral less-loaded cartilage. Among 92 putative N-glycans observed by MALDI-MSI, 3 complex-type N-glycans, (Hex)4(HexNAc)3, (Hex)4(HexNAc)4, and (Hex)5(HexNAc)4, and 1 oligomannose-type N-glycan, (Hex)9(HexNAc)2, were significantly higher in intensity in the medial cartilage compared to the lateral cartilage, whereas 2 tetra-antennary fucosylated-type N-glycans, (Hex)3(HexNAc)6(Fuc)2 and (Hex)3(HexNAc)6(Fuc)3, were significantly higher in intensity in the lateral cartilage than the medial cartilage. Our findings indicate that complex-type N-glycans are associated with higher severity of cartilage degeneration and may influence the cellular processes of KOA.

Benign Brain and Spinal Tumors Originating from Bone or Cartilage.

Benign osseocartilaginous tumors of the spine are overall uncommon, representing between 1 and 13% of all primary bone tumors and less than 10% of all spinal tumors. Tumors in this category include osteoblastic lesions such as the related osteoid osteoma and osteoblastoma, and cartilage-forming lesions including osteochondroma, chondroma, and chondroblastoma. Aneurysmal bone cysts, giant cell tumors of bone, and eosinophilic granulomas also comprise benign tumors of the spine arising from bone. There is significant heterogeneity in the epidemiology, molecular biology, imaging features, and optimal treatment of these lesions. For example, osteoid osteoma is characterized by high expression of the cyclooxygenase enzymes, making it amenable to treatment with anti-inflammatory drugs initially, whereas other lesions such as osteoblastoma may require intralesional curettage or en bloc resection sooner. Generally, en bloc resection is preferred when possible to minimize risk of recurrence. Further, some tumors may arise in the setting of syndromic conditions, such as multiple chondromas arising in Ollier disease or Maffucci syndrome, or as part of genetic disorders, such as osteochondromas in the context of hereditary multiple exostosis. These lesions may present with local pain, cause neurological compromise or be discovered incidentally on routine imaging. The Enneking classification and Weinstein-Boriani-Biagini system are routinely used to classify lesions and assist in surgical planning. More novel techniques such as radiofrequency ablation and laser photocoagulation have been applied for the treatment of osteoid osteoma and may have utility in the treatment of other lesion types. A multidisciplinary approach is critical in the management of benign lesions of the spine, and both chemotherapeutic and surgical approaches are routinely used.

Malignant Brain and Spinal Tumors Originating from Bone or Cartilage.

Malignant bone tumors affecting the brain and spine are a rare and exceedingly difficult-to-treat group of diseases. Most commonly consisting of chordoma and chondrosarcoma, these tumors also include giant-cell tumors and osteosarcomas. This chapter will cover the background, epidemiology, genetics, molecular biology, histopathology, radiographic features, clinical manifestations, therapeutic approaches, and clinical management of each entity.