Cartilage Synthesis Research Articles

Inflammatory Pathways in Knee Osteoarthritis: Potential Targets for Treatment.

Osteoarthritis (OA) of the knee is a wide-spread, debilitating disease that is prominent in Western countries. It is associated with old age, obesity, and mechanical stress on the knee joint. By examining the recent literature on the effect of the anti-inflammatory prostaglandins 15d-PGJ2 and Δ12-PGJ2, we propose that new therapeutic agents for this disease could facilitate the transition from the COX-2-dependent pro-inflammatory synthesis of the prostaglandin PGE2 (catalyzed by mPGES-1), to the equally COX-2-dependent synthesis of the aforementioned anti-inflammatory prostaglandins. This transition could be instrumental in halting the breakdown of cartilage via matrix metalloproteinases (MMPs) and aggrecanases, as well as promoting the matrix regeneration and synthesis of cartilage by chondrocytes. Another desirable property of new OA therapeutics could involve the recruitment of mesenchymal stem cells to the damaged cartilage and bone, possibly resulting in the generation of chondrocytes, synoviocytes, and, in the case of bone, osteoblasts. Moreover, we propose that research promoting this transition from pro-inflammatory to anti-inflammatory prostaglandins could aid in the identification of new OA therapeutics.

The lower cartilage synthesis, but not higher cartilage destruction, is associated with the knee joint space width in men in early forties without knee pain

The lower cartilage synthesis, but not higher cartilage destruction, is associated with the knee joint space width in men in early forties without knee pain

Cartilage synthesis in hyaluronic acid-tyramine constructs.

The objective of this study was to determine the potential for cartilage production within a hyaluronic acid-tyramine (HA-Tyr) hydrogel scaffold. Chondrocytes were encapsulated within HA-Tyr hydrogels and subcutaneously implanted in mice. The HA-Tyr hydrogels were formed by the oxidative coupling of Tyr moieties catalyzed by hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). Harvested constructs were shown to achieve a glycosaminoglycan (GAG) content of 1.2 wt%, and they demonstrated 40% of the collagen content of normal articular cartilage, including the presence of Type II collagen, which is the characteristic of articular cartilage. Matrix production was found to be influenced by the initial cell density, scaffold degradation rate and Type II collagen concentration. Injectability was also imparted to the system by delivering HRP through thermoresponsive liposomes. The method of HRP delivery, either by simple addition or through thermoresponsive liposomes, was not shown to have an effect on matrix production.

Shear and Compression Bioreactor for Cartilage Synthesis.

Mechanical forces, including hydrodynamic shear, hydrostatic pressure, compression, tension, and friction, can have stimulatory effects on cartilage synthesis in tissue engineering systems. Bioreactors capable of exerting forces on cells and tissue constructs within a controlled culture environment are needed to provide appropriate mechanical stimuli. In this chapter, we describe the construction, assembly, and operation of a mechanobioreactor providing simultaneous dynamic shear and compressive loading on developing cartilage tissues to mimic the rolling and squeezing action of articular joints. The device is suitable for studying the effects of mechanical treatment on stem cells and chondrocytes seeded into three-dimensional scaffolds.

Evaluation of early changes of cartilage biomarkers following arthroscopic meniscectomy in young Egyptian adults

BackgroundThe metabolic imbalance in the articular cartilage following meniscectomy includes an increase in cartilage degradation with an insufficient reparative or anabolic response resulting in structural, biochemical and mechanical changes that can progress from pre-clinical, to pre-radiographic, to radiographic damage of the joint. PurposeTo evaluate combinations of imaging and biochemical biomarkers for cartilage breakdown, synthesis and quantity in the early period of post-arthroscopic meniscectomy. Subjects and methodsTwenty young adults (three of them were females) who underwent unilateral arthroscopic partial meniscectomy were evaluated. The patients had a mean age of 32.5years (range, 24–39), mean BMI of 28.5kg/m2 (range, 24–34). Preoperative and six months postoperative US and MRI-based markers (cartilage thickness and volume, respectively) were quantified for medial and lateral tibio-femoral compartments for both knees. Preoperative, three and six months postoperative biochemical markers serum assays were measured; COMP and Col II (cartilage matrix breakdown) and PIICP (cartilage synthesis). These three markers were measured in an age, sex and BMI matched twenty healthy subjects for comparison. ResultsThe meniscectomized knees had significantly lower total knee cartilage volume, P<0.05 but non-significant mean thickness than the intact contralateral knees. Among the individual biochemical markers, PIICP had the highest significant diagnostic accuracy quantified as the area under the receiver-operator characteristics curve (AUC) of 0.75 (95% confidence interval: 0.509–0.912) higher than all others, P<0.05 to distinguish subjects with progressive cartilage loss from non-progressors. Diagnostically, ratio of COMP and Col II to PIICP scored AUC of 0.90 (0.69–0.98, higher than PIICP: P=0.0001). For prediction of cartilage loss, none of the individual markers could be used. ConclusionCartilage volume loss by MRI combined with changes in cartilage matrix turnover detected by molecular biomarkers may reflect the initial changes associated with cartilage degeneration that account for early OA.

Study on the pattern of radiological changes in osteoarthritis of knee joint

Knee osteoarthritis (OA) is one of the frequent and functionally impairing disorders of the musculoskeletal system and characterized by an imbalance between the synthesis and degradation of the articular cartilage. The present study was conducted on the pattern of radiological changes in OA of knee joint patients attending in the department of Physical Medicine &amp; Rehabilitation of Bangabandhu Sheikh Mujib Medical University. Structural changes of articular cartilage were assessed by the sequence of changes in the knee joint manifested as sclerosis, osteophytes formation, and joint space narrowing and joint space erosion by a radiographic examination. Osteophytes were more common in medial condyle in 46-61 age group (73.68%) and male patients of some age group showed higher rate of development of osteophytes in intercondylar area. Narrowing of joint space were more in medial tibiofemoral compartment (59.82%) in the 46-61 age group (70.98%), where as erosion was found higher in medial tibiofemoral compartment (70%) and more in male patients (36%). The findings of this study as revealed by the standard radiographic imaging of formation of osteophytes, joint space narrowing and joint space erosion lead to the recommendation that the problem is increasing with age. However, more studies are required for the purpose specifying medical treatment using appropriate appliances under close supervision of a physical medicine specialist. DOI: http://dx.doi.org/10.3329/bmj.v42i1.18972 Bangladesh Med J. 2013 Jan; 42 (1): 14-17

Runx2 regulates endochondral ossification through control of chondrocyte proliferation and differentiation.

Synthesis of cartilage by chondrocytes is an obligatory step for endochondral ossification. Global deletion of the Runx2 gene results in complete failure of the ossification process, but the underlying cellular and molecular mechanisms are not fully known. Here, we elucidated Runx2 regulatory control distinctive to chondrocyte and cartilage tissue by generating Runx2 exon 8 floxed mice. Deletion of Runx2 gene in chondrocytes caused failure of endochondral ossification and lethality at birth. The limbs of Runx2(ΔE8/ΔE8) mice were devoid of mature chondrocytes, vasculature, and marrow. We demonstrate that the C-terminus of Runx2 drives its biological activity. Importantly, nuclear import and DNA binding functions of Runx2 are insufficient for chondrogenesis. Molecular studies revealed that despite normal levels of Sox9 and PTHrP, chondrocyte differentiation and cartilage growth are disrupted in Runx2(ΔE8/ΔE8) mice. Loss of Runx2 in chondrocytes also impaired osteoprotegerin-receptor activator of NF-κB ligand (OPG-RANKL) signaling and chondroclast development. Dwarfism observed in Runx2 mutants was associated with the near absence of proliferative zone in the growth plates. Finally, we show Runx2 directly regulates a unique set of cell cycle genes, Gpr132, Sfn, c-Myb, and Cyclin A1, to control proliferative capacity of chondrocyte. Thus, Runx2 is obligatory for both proliferation and differentiation of chondrocytes.

Extracellular matrix production in vitro in cartilage tissue engineering

Cartilage tissue engineering is arising as a technique for the repair of cartilage lesions in clinical applications. However, fibrocartilage formation weakened the mechanical functions of the articular, which compromises the clinical outcomes. Due to the low proliferation ability, dedifferentiation property and low production of cartilage-specific extracellular matrix (ECM) of the chondrocytes, the cartilage synthesis in vitro has been one of the major limitations for obtaining high-quality engineered cartilage constructs. This review discusses cells, biomaterial scaffolds and stimulating factors that can facilitate the cartilage-specific ECM production and accumulation in the in vitro culture system. Special emphasis has been put on the factors that affect the production of ECM macromolecules such as collagen type II and proteoglycans in the review, aiming at providing new strategies to improve the quality of tissue-engineered cartilage.

Serum biochemical markers of joint metabolism and inflammation in relation to clinical symptoms and physical function in adults with symptomatic knee osteoarthritis

Purpose: To date, the majority of osteoarthritis (OA) biomarker research has examined associations between biomarker levels and radiographic parameters. While radiography provides information on the structural burden of disease, it is insensitive to small changes in cartilage metabolism and does not always correlate with the most significant clinical expression in OA, pain. The purpose of this study was to investigate the associations between joint metabolism and inflammation with pain and physical function in adults with painful knee OA. This is in support of qualifying burden of disease biomarkers with clinical variables to support the study, management, and understanding of disease pathology in OA. Methods: The study used baseline data from 54 adults with knee OA participating in a nutrition intervention study. The 100 mm visual analogue scale version of theWestern Ontario andMcMaster University Osteoarthritis Index (WOMAC) was used to assess pain, stiffness, and physical disability. A minimumWOMAC pain score of 125 was used as a cutoff for participant inclusion. Physical functionwas assessed with a 6minute walk test (:6MWT) and stair climb task (SCT). Serum concentrations of biomarkers included measures of cartilage degradation (cartilage oligomeric matrix protein [COMP]), cartilage synthesis (typeIIA collagen N-propeptide [PIIANP]), synovial metabolism (hyaluronic acid [HA]), cartilage degrading enzyme levels (matrix metalloproteinase 3 [MMP-3]), and inflammation (C-reactive protein [CRP]). COMP, PIIANP, HA, and MMP-3 were measured by enzyme-linked immunosorbent assay and CRP was measured by an immunoturbidimetric assay. Correlations between biomarkers and clinical variables were assessed using Spearman correlation coefficients. Results: Participants (38 females and 16 males) had a mean age of 60 11.9 years, BMI of 32.6 7.5 kg/m2, disease duration of 86.6 112.2 months, and WOMAC pain score of 193.4 94.04 mm. Higher serum MMP-3 levels were significantly associated with higher WOMAC pain scores (R 1⁄4 0.27, p 1⁄4 0.05), controlling for age and body mass index (BMI). Higher levels of serum HA were significantly associated with decreased walking distance in the :6MWT (R 1⁄4 -0.35, p 1⁄4 0.01) and longer time taken in the SCT (R 1⁄4 0.31, p 1⁄4 0.02), when controlling for age and BMI. Higher CRP levels were significantly associated with higher WOMAC physical disability score (R 1⁄4 0.34, p 1⁄4 0.01) and worse performance in the :6MWT (R1⁄4 -0.38, p1⁄4 0.005) and SCT (R1⁄4 0.44, p1⁄4 0.001) when age was controlled for, but these associations were not significant when BMI was controlled for. COMP and PIIANP were not significantly associated with any clinical variables analyzed. Conclusion: SerumMMP-3 levels were associated with pain and serum HA levels were associated with physical functioning in adults who suffer from mild to moderate pain and impaired physical functioning from knee OA. Previous studies have shown that HA and MMP-3 are related to structural knee parameters in OA. Therefore, results from this study demonstrate that serum HA and MMP-3 also have potential as qualified burden of disease biomarkers that are clinically meaningful. (Research supported by the Ontario Ministry of Agriculture, Food and Rural Affairs, project #200121).

Definición, etiopatogenia, clasificación y formas de presentación

Osteoarthritis is defined as a degenerative process affecting the joints as a result of mechanical and biological disorders that destabilize the balance between the synthesis and degradation of joint cartilage, stimulating the growth of subchondral bone; chronic synovitis is also present. Currently, the joint is considered as a functional unit that includes distinct tissues, mainly cartilage, the synovial membrane, and subchondral bone, all of which are involved in the pathogenesis of the disease.Distinct risk factors for the development of osteoarthritis have been described: general, unmodifiable risk factors (age, sex, and genetic makeup), general, modifiable risk factors (obesity and hormonal factors) and local risk factors (prior joint anomalies and joint overload). Notable among the main factors related to disease progression are joint alignment defects and generalized osteoarthritis.Several classifications of osteoarthritis have been proposed but none is particularly important for the primary care management of the disease. These classifications include etiological (primary or idiopathic forms and secondary forms) and topographical (typical and atypical localizations) classifications, the Kellgren and Lawrence classification (radiological repercussions) and that of the American College of Rheumatology for osteoarthritis of the hand, hip and knee.The prevalence of knee osteoarthritis is 10.2% in Spain and shows a marked discrepancy between clinical and radiological findings. Hand osteoarthritis, with a prevalence of symptomatic involvement of around 6.2%, has several forms of presentation (nodal osteoarthritis, generalized osteoarthritis, rhizarthrosis, and erosive osteoarthritis). Symptomatic osteoarthritis of the hip affects between 3.5% and 5.6% of persons older than 50 years and has different radiological patterns depending on femoral head migration.

A comparative study between Antioxidant vitamin and Kellgren–Lawrence grading scale in knee osteoarthritis patients

Osteoarthritis (OA) is a strongly age-related joint disorder that is defined as a gradual loss of articular cartilage. Current concepts of the pathogenic mechanisms of OA suggest that there isa shift in the homeostatic balance between the destruction and synthesis of bone and cartilage,with a net progressive destruction of these tissues. Recent studies of the biology of chondrocytes show that these cells actively produce reactive oxygen species (ROS). ROS are capable of inducing apoptotic cell death in chondrocytes, but more important, they can result in the degradation of aggrecan and collagen. Micronutrient antioxidants such as alpha- Tocopherol (Vitamin E) and Vitamin C also act to reduce the effects of ROS. A hospital based case control study was conducted in Burdwan Medical College, West Bengal, India on 76 postmenopausal women aged 45–70 years suffering from Osteoarthritis (OA) of the knee joint, which was diagnosed from symptoms, clinical examinations and radiographic findings. The 151 controls were selected from the healthy persons .plasma vitamin C and serum vitamin E ware measured.. Knee joint radiographs were evaluated with the Kellgren–Lawrence grading scale .Furthermore both were correlated with Kellgren–Lawrence grading scale to find out possible association between the antioxidant vitamins and the disease progression. Results showed that there was a significant decrease in antioxidant vitamin levels in patients with knee joint osteoarthritis as compared to the controls suggests that treatment with antioxidants in the initial stages of the disease may be useful as secondary therapy. Both antioxidant vitamins showed negative correlation with Kellgren–Lawrence grading. Both vitamins decreased with increasing Kellgren–Lawrence grade. So antioxidant vitamin can be use to assess the disease severity. DOI: http://dx.doi.org/10.3329/bjms.v13i1.14046 Bangladesh Journal of Medical Science Vol. 13 No. 01 January2014: 30-35

Link Protein N-terminal Peptide Binds to Bone Morphogenetic Protein (BMP) Type II Receptor and Drives Matrix Protein Expression in Rabbit Intervertebral Disc Cells

Intervertebral disc (IVD) degeneration and associated spinal disorders are leading sources of morbidity, and they can be responsible for chronic low back pain. Treatments for degenerative disc diseases continue to be a challenge. Intensive research is now focusing on promoting regeneration of degenerated discs by stimulating production of the disc matrix. Link protein N-terminal peptide (LPP) is a proteolytic fragment of link protein, an important cross-linker and stabilizer of the major structural components of cartilage, aggrecan and hyaluronan. In this study we investigated LPP action in rabbit primary intervertebral disc cells cultured ex vivo in a three-dimensional alginate matrix. Our data reveal that LPP promotes disc matrix production, which was evidenced by increased expression of the chondrocyte-specific transcription factor SOX9 and the extracellular matrix macromolecules aggrecan and collagen II. Using colocalization and pulldown studies we further document a noggin-insensitive direct peptide-protein association between LPP and BMP-RII. This association mediated Smad signaling that converges on BMP genes leading to expression of BMP-4 and BMP-7. Furthermore, through a cell-autonomous loop BMP-4 and BMP-7 intensified Smad1/5 signaling though a feedforward circuit involving BMP-RI, ultimately promoting expression of SOX9 and downstream aggrecan and collagen II genes. Our data define a complex regulatory signaling cascade initiated by LPP and suggest that LPP may be a useful therapeutic substitute for direct BMP administration to treat IVD degeneration and to ameliorate IVD-associated chronic low back pain.

Comparing glycine and serine kinetics in adolescent girls and adult women during early and late pregnancy

During pregnancy, glycine (Gly) and serine (Ser) becomes more important because they are the primary suppliers of methyl groups for synthesis of fetal DNA and Gly is also required for collagen synthesis. The objective of this study was to measure and compare Gly and Ser kinetics of pregnant adolescent girls and adult women in the first (13.0±0.4 wk of gestation) and third trimesters (28.8±0.4 wk of gestation). Measurements were made in the fasted state by continuous intravenous infusions of 2H2‐Gly and 15N‐Ser in 11 adolescent girls (17.4±0.1 y of age) and in 10 adult women (25.8±0.5 y of age) for 6 h. Adult women Adolescent girls Flux 1st trimester 3rd trimester 1st trimester 3rd trimester μmol/kg/h Gly 156±14 136±9 165±11 142±7* Ser 129±15 119±13 133±11 111±6 Gly→Ser 4.2±0.6 4.2±0.5 4.3±0.5 4.8±0.4 Ser→Gly 62±9 57±7 70±7 54±3* Different vs. trimester 1 value, P&lt;0.05, paired t‐test. Adolescent girls had significantly slower glycine flux and made less glycine from serine in the 3rd trimester (P &lt; 0.05). Baby's birth length was significantly shorter in adolescent girl (P = 0.04), and baby's birth weight was 7% less compared with mean values of adult women. These findings suggest that pregnant adolescents could not maintain Gly production in late pregnancy compared to early pregnancy, which makes their fetus more vulnerable to impaired cartilage synthesis, hence linear growth. Supported by USDA Grant # 58–6250‐6001

Relationships amongst osteoarthritis biomarkers, dynamic knee joint load, and exercise: results from a randomized controlled pilot study

BackgroundLittle is known about the relationships of circulating levels of biomarkers of cartilage degradation with biomechanical outcomes relevant to knee osteoarthritis (OA) or biomarker changes following non-pharmacological interventions. The objectives of this exploratory, pilot study were to: 1) examine relationships between biomarkers of articular cartilage degradation and synthesis with measures of knee joint load during walking, and 2) examine changes in these biomarkers following 10 weeks of strengthening exercises.MethodsSeventeen (8 male, 9 female; 66.1 +/- 11.3 years of age) individuals with radiographically-confirmed medial tibiofemoral OA participated. All participants underwent a baseline testing session where serum and urine samples were collected, followed by a three-dimensional motion analysis. Motion analysis was used to calculate the external knee adduction moment (KAM) peak value and impulse. Following baseline testing, participants were randomized to either 10 weeks of: 1) physiotherapist-supervised lower limb muscle strengthening exercises, or 2) no exercises (control). Identical follow-up testing was conducted 11 weeks after baseline. Biomarkers included: urinary C-telopeptide of type II collagen (uCTX-II) and type II collagen cleavage neoepitope (uC2C), serum cartilage oligomeric matrix protein (sCOMP), serum hyaluronic acid (sHA) and serum C-propeptide of type II procollagen (sCPII). Linear regression analysis was used to examine relationships between measures of the KAM and biomarker concentrations as baseline, as well as between-group differences following the intervention.ResultsKAM impulse predicted significant variation in uCTX-II levels at baseline (p = 0.04), though not when controlling for disease severity and walking speed (p = 0.33). KAM impulse explained significant variation in the ratio uCTX-II;sCPII even when controlling for additional variables (p = 0.04). Following the intervention, changes in sCOMP were significantly greater in the exercise group compared to controls (p = 0.04). On average those in the control group experienced a slight increase in sCOMP and uCTX-II, while those in the exercise group experienced a reduction. No other significant findings were observed.ConclusionsThis research provides initial evidence of a potential relationship between uCTX-II and knee joint load measures in patients with medial tibiofemoral knee OA. However, this relationship became non-significant after controlling for disease severity and walking speed, suggesting further research is necessary. It also appears that sCOMP is amenable to change following a strengthening intervention, suggesting a potential beneficial role of exercise on cartilage structure.Trial registrationClinicaltrials.gov NCT01241812

Regulation of Xylosyltransferase I Gene Expression by Interleukin 1β in Human Primary Chondrocyte Cells: MECHANISM AND IMPACT ON PROTEOGLYCAN SYNTHESIS

Xylosyltransferase I (XT-I) is an essential enzyme of proteoglycan (PG) biosynthesis pathway catalyzing the initial and rate-limiting step in glycosaminoglycan chain assembly. It plays a critical role in the regulation of PG synthesis in cartilage; however, little is known about underlying mechanism. Here, we provide evidence that, in human primary chondrocytes, IL-1β regulates XT-I gene expression into an early phase of induction and a late phase of down-regulation. Based on promoter deletions, the region up to -850 bp was defined as a major element of XT-I gene displaying both constitutive and IL-1β-regulated promoter activity. Point mutation and signaling analyses revealed that IL-1β-induced promoter activity is achieved through AP-1 response elements and mediated by SAP/JNK and p38 signaling pathways. Transactivation and chromatin immunoprecipitation assays indicated that AP-1 is a potent transactivator of XT-I promoter and that IL-1β-induced activity is mediated through increased recruitment of AP-1 to the promoter. Finally, we show that Sp3 is a repressor of XT-I promoter and bring evidence that the repressive effect of IL-1β during the late phase is mediated through Sp3 recruitment to the promoter. This suggests that modulation of Sp3 in cartilage could prevent IL-1β inhibition of PG synthesis and limit tissue degradation.

A study to assess relationship between Synovial fluid lipid peroxidation marker and the severity of knee osteoarthritis

Osteoarthritis is the most common cause of pain due to arthritis in women. Its high prevalence especially in the postmenopausal women, and the high rate of disability associated with the disease makes it a diagnostic and therapeutic priority. A hospital based cross sectional study was conducted in Burdwan Medical College, West Bengal, India on 76 postmenopausal women aged 45-70 years suffering from Osteoarthritis (OA) of the knee joint, which was diagnosed from symptoms, clinical examinations and radiographic findings. 150 subjects undergoing knee joint arthroscopy for chronic knee pain, meniscal tears or anterior cruciate ligament reconstruction were taken as control .Synovial fluid malondialdehyde (MDA) was measured as an index of synovial fluid lipid peroxidation. The width of knee joint space was measured from the radiographic plates to assess the disease severity. Knee joint radiographs were evaluated with the Kellgren-Lawrence grading scale .Furthermore both were correlated with oxidative stress parameters ,synovial fluid MDA levels to find out possible association between the oxidative stress induced damage and the disease progression. Results showed that there was a significant increase in MDA levels in patients with knee joint osteoarthritis as compared to the controls. Synovial MDA showed positive correlation with Kellgren-Lawrence grading and negative correlation with knee joint space width. The joint space width decreased and synovial MDA increase with increasing Kellgren-Lawrence grad. especially in the elderly, and the high rate of disability related to disease makes it a leading cause of disability, suffering and morbidity. Over 40% of the Indian populations in the age group of 70 years or above suffer from osteoarthritis 3 it is characterized by low-grade inflammation resulting in pain in the joints. Pain is caused due to wear and destruction of the joint cartilage as well as destruction or decrease of synovial fluid that lubricates those joints. Current concepts of the pathogenic mechanisms of OA suggest that there is a shift in the homeostatic balance between the destruction and synthesis of bone and cartilage, with a net progressive destruction of these tissues 4 Recent studies of the biology of chondrocytes show that these cells actively produce reactive oxygen species (ROS), including superoxide anions, hydrogen peroxide, hydroxyl radicals, and nitric oxide 5 which may be detected in the synovial fluid of the knee joint. However, few studies have been done to establish the relationship between oxidative stress and clinical severity of disease. Aim of this study was to analyze the relationship between oxidative stress in the knee joints and the clinical severity of osteoarthritis. The clinical severity of OA was evaluated by measuring the width of knee joint space and by utilizing the Kellgren-Lawrence grading scale. The width of knee joint space was measured from the radiographs of the same. The severity of OA was graded by the Kellgren-Lawrence grading scale 6

Prognostic biomarkers in osteoarthritis

Identification of patients at risk for incident disease or disease progression in osteoarthritis remains challenging, as radiography is an insensitive reflection of molecular changes that presage cartilage and bone abnormalities. Thus there is a widely appreciated need for biochemical and imaging biomarkers. We describe recent developments with such biomarkers to identify osteoarthritis patients who are at risk for disease progression. The biochemical markers currently under evaluation include anabolic, catabolic, and inflammatory molecules representing diverse biological pathways. A few promising cartilage and bone degradation and synthesis biomarkers are in various stages of development, awaiting further validation in larger populations. A number of studies have shown elevated expression levels of inflammatory biomarkers, both locally (synovial fluid) and systemically (serum and plasma). These chemical biomarkers are under evaluation in combination with imaging biomarkers to predict early onset and the burden of disease. Prognostic biomarkers may be used in clinical knee osteoarthritis to identify subgroups in whom the disease progresses at different rates. This could facilitate our understanding of the pathogenesis and allow us to differentiate phenotypes within a heterogeneous knee osteoarthritis population. Ultimately, such findings may help facilitate the development of disease-modifying osteoarthritis drugs (DMOADs).

Ionizing radiation causes active degradation and reduces matrix synthesis in articular cartilage

Purpose: Little is known regarding radiation effects on adult articular (joint) cartilage, though joint damage has been reported following cancer treatment or occupational exposures. The aim of this study was to determine if radiation can reduce cartilage matrix production, induce cartilage degradation, or interfere with the anabolic effects of IGF-1.Materials and methods: Isolated chondrocytes cultured in monolayers and whole explants harvested from ankles of human donors and knees of pigs were irradiated with 2 or 10 Gy γ-rays, with or without IGF-1 stimulation. Proteoglycan synthesis and IGF-1 signaling were examined at Day 1; cartilage degradation throughout the first 96 hours.Results: Human and pig cartilage responded similarly to radiation. Cell viability was unchanged. Basal and IGF-1 stimulated proteoglycan synthesis was reduced following exposure, particularly following 10 Gy. Both doses decreased IGF-induced Akt activation and IGF-1 receptor phosphorylation. Matrix metalloproteinases (ADAMTS5, MMP-1, and MMP-13) and proteoglycans were released into media after 2 and 10 Gy.Conclusions: Radiation induced an active degradation of cartilage, reduced proteoglycan synthesis, and impaired IGF-1 signaling in human and pig chondrocytes. Lowered Akt activation could account for decreased matrix synthesis. Radiation may cause a functional decline of cartilage health in joints after exposure, contributing to arthropathy.

Understanding CpG Methylation in the Context of Osteoarthritis

Worldwide, osteoarthritis (OA) affects approxi‐ mately 40% of people older than 70 years and is therefore the most common form of arthritis. OA is a complex degenerative disease of the joint but is epitomized by focal degradation of articular cartilage [1]. Cartilage itself is a highly special‐ ized tissue composed of an extracellular matrix (ECM) rich in type‐II collagen and the proteo‐ glycan aggrecan. The tissue is sparsely populated by the sole resident cell, the chondrocyte, which maintains tissue integrity by balancing the syn‐ thesis and degradation of ECM components [2]. In OA, this balance is perturbed in favor of ECM degradation, mediated by proteolytic enzymes including MMP13 and ADAMTS5, which prob‐ ably degrade the type‐II collagen and aggrecan, respectively [3]. Inhibition of metalloproteinase activity should protect against cartilage destruc‐ tion, but has failed in clinical trials in part owing to nonselectivity and resulting adverse side effects [4]. Amongst other things, this has led to the sug‐ gestion that targeting the regulation of expression of specific proteases, or regulating factors, could be an important therapeutic option to slow or halt OA progression. There is an urgent need for such disease‐modifying, noninvasive treatments for OA since the only current therapy is joint replacement surgery. Epigenetic regulation involves three basic mechanisms: DNA methylation, histone modi‐ fications and ncRNAs. DNA methylation rep‐ resents the most stable epigenetic modification and involves the addition of a methyl group to the cytosine at CpG dinucleotides, converting cytosine to 5‐methylcytosine. This functions to disrupt the binding of transcription factors or enhance the binding of repressors, leading to an altered transcriptional state of the cell [5]. In terms of OA research, a number of studies have inves‐ tigated the role that epigenetics, especially DNA methylation, could play in OA, particularly in terms of regulating the balance between matrix synthesis and degradation in cartilage. These studies have focused on correlating DNA methyla‐ tion status with gene expression at a few candidate genes (loci), including those coding for aggrecan, collagens, MMPs, LEPTIN, SOX9 and RUNX2 [6]. Broadly, these works have shown a correlation between promoter methylation and the expression of the associated gene. Recently, we took this work one step further and identified a specific differen‐ tially methylated CpG locus within the MMP13 promoter whose methylation status regulates the expression of the gene by controlling the binding of the transcriptional regulator CREB [7]. These and ongoing ‘candidate’ gene studies will continue to identify differentially methylated regions that may be important in onset of the disease.

Synovial TGF-β1 and MMP-3 levels and their correlation with the progression of temporomandibular joint osteoarthritis combined with disc displacement: A preliminary study

Osteoarthritis (OA) is a slow progressing degenerative disease that affects the joints, including the temporomandibular joint. In the present study, transforming growth factor-β1 (TGF-β1) and matrix metalloproteinase 3 (MMP-3) in synovial fluid (SF) were examined in detecting cartilage synthesis and degradation in progression of temporomandibular joint osteoarthritis (TMJ OA) combined with disc displacement (DD) diseases. SF was obtained from 16 patients with TMJ OA combined with DD and 10 normal volunteers. TGF-β1 and MMP-3 levels were measured by enzyme-linked immunosorbent assay. In addition, TMJ OA combined with DD was classified into three stages based on radiographic signs on the preoperative tomograms and surgical findings at operation, and different treatment options were administered according to the stages. SF from TMJs with TMJ OA combined with DD showed higher levels of TGF-β1 and MMP-3 compared with the asymptomatic control TMJs. With the progression of TMJ OA combined with DD, TGF-β1 levels in SF were lower, while MMP-3 levels in SF were significantly higher. In conclusion, these data suggest that MMP-3 is not only involved in the pathological destruction process of TMJ OA combined with DD initially, but also has a positive correlation with the degree of pathological changes. Furthermore, a significant increase of TGF-β1 levels was found in the SF that were able to counteract the deleterious effects of MMP-3 at the early stage of TMJ OA combined DD, providing the scientific basis on repositioning displaced disc as early as possible for these patients.