The effect of the pro-inflammatory cytokine tumor necrosis factor-alpha on human joint capsule myofibroblasts

Introduction  

Previous studies have shown that the number of myoblastically differentiated fibroblasts known as myofibroblasts (MFs) is significantly increased in stiff joint capsules, indicating their crucial role in the pathogenesis of post-traumatic joint stiffness. Although the mode of MFs' function has been well defined for different diseases associated with tissue fibrosis, the underlying mechanisms of their regulation in the pathogenesis of post-traumatic joint capsule contracture are largely unknown.     

Promising potential of new generation translocator protein tracers providing enhanced contrast of arthritis imaging by positron emission tomography in a rat model of arthritis

Introduction

The role of popliteal cysts and subgastrocnemius bursitis in knee joint homeostasis is uncertain. The aim of this study is to describe cross-sectional associations between popliteal cysts, subgastrocnemius bursitis, knee symptoms and structural abnormalities in older adults.

Methods

A cross-sectional sample of 900 randomly-selected subjects (mean age 63 years, 48% female) were studied. Knee pain, stiffness and dysfunction were assessed by self-administered Western Ontario McMaster Osteoarthritis Index (WOMAC) questionnaire. Radiographic knee osteophyte and joint space narrowing (JSN) were recorded. Magnetic resonance imaging (MRI) was utilized to assess popliteal cysts, subgastrocnemius bursitis, cartilage defects and bone marrow lesions (BMLs).

Results

Popliteal cysts were present in 11.7% and subgastrocnemius bursitis in 12.7% of subjects. Subgastrocnemius bursitis was more common in those with popliteal cyst (36.2% versus 9.7%, P <0.01). In multivariable analyses, popliteal cysts were significantly associated with increased osteophytes in both medial and lateral tibiofemoral compartments while subgastrocnemius bursitis was associated with increased osteophytes and JSN in the medial tibiofemoral compartment. Both were significantly associated with cartilage defects in all compartments, and with BMLs in the medial tibiofemoral compartment. Furthermore, both popliteal cysts and subgastrocnemius bursitis were significantly associated with increased weight-bearing knee pain but these associations became non-significant after adjustment for cartilage defects and BMLs.

Conclusions

Popliteal cysts and subgastrocnemius bursitis are associated with increased symptoms as well as radiographic and MRI-detected joint structural abnormalities. Longitudinal data will help resolve if they are a consequence or a cause of knee joint abnormalities.     

Anti-Inflammatory mechanisms of the proteinase-activated receptor 2-inhibiting peptide in human synovial cells

Background  

Osteoarthritis (OA) is a degenerative joint disease which affects the entire joint structure, including the synovial membrane. Disease progression was shown to involve inflammatory changes mediated by proteinase-activated receptor (PAR)-2. Previous studies demonstrated that PAR-2 messenger (m)RNA and protein levels increased in OA synovial cells, suggesting that PAR-2 is a potential therapeutic target of the disease.     

Popliteal cysts and subgastrocnemius bursitis are associated with knee symptoms and structural abnormalities in older adults: a cross-sectional study

Introduction

The role of popliteal cysts and subgastrocnemius bursitis in knee joint homeostasis is uncertain. The aim of this study is to describe cross-sectional associations between popliteal cysts, subgastrocnemius bursitis, knee symptoms and structural abnormalities in older adults.

Methods

A cross-sectional sample of 900 randomly-selected subjects (mean age 63 years, 48% female) were studied. Knee pain, stiffness and dysfunction were assessed by self-administered Western Ontario McMaster Osteoarthritis Index (WOMAC) questionnaire. Radiographic knee osteophyte and joint space narrowing (JSN) were recorded. Magnetic resonance imaging (MRI) was utilized to assess popliteal cysts, subgastrocnemius bursitis, cartilage defects and bone marrow lesions (BMLs).

Results

Popliteal cysts were present in 11.7% and subgastrocnemius bursitis in 12.7% of subjects. Subgastrocnemius bursitis was more common in those with popliteal cyst (36.2% versus 9.7%, P <0.01). In multivariable analyses, popliteal cysts were significantly associated with increased osteophytes in both medial and lateral tibiofemoral compartments while subgastrocnemius bursitis was associated with increased osteophytes and JSN in the medial tibiofemoral compartment. Both were significantly associated with cartilage defects in all compartments, and with BMLs in the medial tibiofemoral compartment. Furthermore, both popliteal cysts and subgastrocnemius bursitis were significantly associated with increased weight-bearing knee pain but these associations became non-significant after adjustment for cartilage defects and BMLs.

Conclusions

Popliteal cysts and subgastrocnemius bursitis are associated with increased symptoms as well as radiographic and MRI-detected joint structural abnormalities. Longitudinal data will help resolve if they are a consequence or a cause of knee joint abnormalities.     

Epitope spreading to citrullinated antigens in mouse models of autoimmune arthritis and demyelination

Introduction  

Anti-citrullinated protein antibodies have a diagnostic role in rheumatoid arthritis (RA); however, little is known about their origins and contribution to pathogenesis. Citrullination is the post-translational conversion of arginine to citrulline by peptidyl arginine deiminase, and increased citrullination of proteins is observed in the joint tissue in RA and in brain tissue in multiple sclerosis (MS).     

Effects of long-term spaceflight on mechanical properties of muscles in humans

The effects of long-term spaceflight(90-180 days) on the contractile and elastic characteristics ofthe human plantarflexor muscles were studied in 14 cosmonauts beforeand 2-3 days after landing. Despite countermeasures practicedaboard, spaceflight was found to induce a decrease in maximal isometrictorque (17%), whereas an index of maximal shortening velocity wasfound to increase (31%). In addition, maximal muscle activationevaluated during isokinetic tests decreased by 39%. Changes inmusculotendinous stiffness and whole joint stiffness were characterizedby means of quick-release movements and sinusoidal perturbations.Musculotendinous stiffness was found to be increased by 25%. Wholejoint stiffness decreased under passive conditions (21%), whereaswhole joint stiffness under active conditions remained unchanged afterspaceflight (1%). This invariance suggests an adaptive mechanism tocounterbalance the decrease in stiffness of passive structures by anincreased active stiffness. Changes in neural drive could participatein this equilibrium.

     

Leg stiffness adjustment for a range of hopping frequencies in humans

The purpose of the present study was to determine how humans adjust leg stiffness over a range of hopping frequencies. Ten male subjects performed in place hopping on two legs, at three frequencies (1.5, 2.2, and 3.0 Hz). Leg stiffness, joint stiffness and touchdown joint angles were calculated from kinetic and/or kinematics data. Electromyographic activity (EMG) was recorded from six leg muscles. Leg stiffness increased with an increase in hopping frequency. Hip and knee stiffnesses were significantly greater at 3.0 Hz than at 1.5 Hz. There was no significant difference in ankle stiffness among the three hopping frequencies. Although there were significant differences in EMG activity among the three hopping frequencies, the largest was the 1.5 Hz, followed by the 2.2 Hz and then 3.0 Hz. The subjects landed with a straighter leg (both hip and knee were extended more) with increased hopping frequency. These results suggest that over the range of hopping frequencies we evaluated, humans adjust leg stiffness by altering hip and knee stiffness. This is accomplished by extending the touchdown joint angles rather than by altering neural activity.     

The tumour-associated glycoprotein podoplanin is expressed in fibroblast-like synoviocytes of the hyperplastic synovial lining layer in rheumatoid arthritis

Introduction  

Activated fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA) share many characteristics with tumour cells and are key mediators of synovial tissue transformation and joint destruction. The glycoprotein podoplanin is upregulated in the invasive front of several human cancers and has been associated with epithelial-mesenchymal transition, increased cell migration and tissue invasion. The aim of this study was to investigate whether podoplanin is expressed in areas of synovial transformation in RA and especially in promigratory RA-FLS.     

Reduced rates of primary joint replacement for osteoarthritis in Italian and Greek migrants to Australia: the Melbourne Collaborative Cohort Study

Introduction  

Racial and ethnic disparities in rates of total joint replacement have been described, but little work has been done in well-established migrant groups. The aim of this study was to compare the rates of primary joint replacement for osteoarthritis for Italian and Greek migrants to Australia and Australian-born individuals.     

Lower limb joint stiffness and muscle co-contraction adaptations to instability footwear during locomotion

Unstable shoes (US) continually perturb gait which can train the lower limb musculature, but muscle co-contraction and potential joint stiffness strategies are not well understood. A shoe with a randomly perturbing midsole (IM) may enhance these adaptations. This study compares ankle and knee joint stiffness, and ankle muscle co-contraction during walking and running in US, IM and a control shoe in 18 healthy females. Ground reaction forces, three-dimensional kinematics and electromyography of the gastrocnemius medialis and tibialis anterior were recorded. Stiffness was calculated during loading and propulsion, derived from the sagittal joint angle-moment curves. Ankle co-contraction was analysed during pre-activation and stiffness phases. Ankle stiffness reduced and knee stiffness increased during loading in IM and US whilst walking (ankle, knee: p = 0.008, 0.005) and running (p < 0.001; p = 0.002). During propulsion, the opposite joint stiffness re-organisation was found in IM whilst walking (both joints p < 0.001). Ankle co-contraction increased in IM during pre-activation (walking: p = 0.001; running: p < 0.001), and loading whilst walking (p = 0.003), not relating to ankle stiffness. Results identified relative levels of joint stiffness change in unstable shoes, providing new evidence of how stability is maintained at the joint level.     

Exercise increases interleukin-10 levels both intraarticularly and peri-synovially in patients with knee osteoarthritis: a randomized controlled trial

Introduction  

The microdialysis method was applied to the human knee joint with osteoarthritis (OA) in order to reveal changes in biochemical markers of cartilage and inflammation, intraarticularly and in the synovium, in response to a single bout of mechanical joint loading.     

Microstructure and mineral composition of dystrophic calcification associated with the idiopathic inflammatory myopathies

Introduction  

Calcified deposits (CDs) in skin and muscles are common in juvenile dermatomyositis (DM), and less frequent in adult DM. Limited information exists about the microstructure and composition of these deposits, and no information is available on their elemental composition and contents, mineral density (MD) and stiffness. We determined the microstructure, chemical composition, MD and stiffness of CDs obtained from DM patients.     

A profile of immune response to herpesvirus is associated with radiographic joint damage in rheumatoid arthritis

Introduction  

Progression of joint damage despite appropriate therapy remains a significant problem for patients with rheumatoid arthritis (RA). This study was undertaken to identify profiles of immune response that correlate with radiographic joint damage as a first step toward the discovery of new pathogenic mechanisms of joint destruction in RA.     

Impact of low-dose prednisolone on bone synthesis and resorption in early rheumatoid arthritis: experiences from a two-year randomized study

Introduction  

Patients with rheumatoid arthritis (RA) have an increased frequency of osteoporosis, mainly because of increased bone resorption. Reduction of disease activity is suggested to reduce bone remodelling. It might also be possible that prednisolone treatment could cause this effect because prednisolone has been shown to arrest the development of joint destruction in early RA. Therefore, we examined the effects of low-dose prednisolone on serum concentrations of bone remodelling markers and insulin-like growth factor-1 (IGF-1) in RA patients in relation to bone mineral density.     

In vivo measurement of bending stiffness in fracture healing

Background  

Measurement of the bending stiffness a healing fracture represents a valid variable in the assessment of fracture healing. However, currently available methods typically have high measurement errors, even for mild pin loosening. Furthermore, these methods cannot provide actual values of bending stiffness, which precludes comparisons among individual fractures. Thus, even today, little information is available with regards to the fracture healing pattern with respect to actual values of bending stiffness. Our goals were, therefore: to develop a measurement device that would allow accurate and sensitive measurement of bending stiffness, even in the presence of mild pin loosening; to describe the course of healing in individual fractures; and help to evaluate whether the individual pattern of bending stiffness can be predicted at an early stage of healing.     

Dynamic activation of bone morphogenetic protein signaling in collagen-induced arthritis supports their role in joint homeostasis and disease

Introduction  

Rheumatoid arthritis is a chronic systemic autoimmune disease affecting peripheral joints and leading to loss of joint function. The severity and outcome of disease are dependent on the balance between inflammatory/destructive and homeostatic or repair pathways. Increasing evidence suggests a role for bone morphogenetic protein (BMP) signaling in joint homeostasis and disease.     

Tensile properties, collagen content, and crosslinks in connective tissues of the immature knee joint

Background

The major connective tissues of the knee joint act in concert during locomotion to provide joint stability, smooth articulation, shock absorption, and distribution of mechanical stresses. These functions are largely conferred by the intrinsic material properties of the tissues, which are in turn determined by biochemical composition. A thorough understanding of the structure-function relationships of the connective tissues of the knee joint is needed to provide design parameters for efforts in tissue engineering.

Methodology/Principal Findings

The objective of this study was to perform a comprehensive characterization of the tensile properties, collagen content, and pyridinoline crosslink abundance of condylar cartilage, patellar cartilage, medial and lateral menisci, cranial and caudal cruciate ligaments (analogous to anterior and posterior cruciate ligaments in humans, respectively), medial and lateral collateral ligaments, and patellar ligament from immature bovine calves. Tensile stiffness and strength were greatest in the menisci and patellar ligament, and lowest in the hyaline cartilages and cruciate ligaments; these tensile results reflected trends in collagen content. Pyridinoline crosslinks were found in every tissue despite the relative immaturity of the joints, and significant differences were observed among tissues. Notably, for the cruciate ligaments and patellar ligament, crosslink density appeared more important in determining tensile stiffness than collagen content.

Conclusions/Significance

To our knowledge, this study is the first to examine tensile properties, collagen content, and pyridinoline crosslink abundance in a direct head-to-head comparison among all of the major connective tissues of the knee. This is also the first study to report results for pyridinoline crosslink density that suggest its preferential role over collagen in determining tensile stiffness for certain tissues.     

Inhibition of Contractile Function in Human Joint Capsule Myofibroblasts by Targeting the TGF-β1 and PDGF Pathways

Background

Contractile myofibroblasts (MFs) accumulate in the joint capsules of patients suffering from posttraumatic joint stiffness. MF activation is controlled by a complex local network of growth factors and cytokines, ending in the increased production of extracellular matrix components followed by soft tissue contracture. Despite the tremendous growth of knowledge in this field, inconsistencies remain in practice and prevention.

Methods and Findings

In this in vitro study, we isolated and cultured alpha-smooth muscle actin (α-SMA) positive human joint capsule MFs from biopsy specimens and investigated the effect of profibrotic and antifibrotic agents on MF function. Both TGF-β1 and PDGF significantly induced proliferation and increased extracellular matrix contraction in an established 3D collagen gel contraction model. Furthermore, both growth factors induced α-SMA and collagen type I gene expression in MFs. TGF-β1 down-regulated TGF-β1 and TGF-β receptor (R) 1 and receptor (R) 2 gene expression, while PDGF selectively down-regulated TGF-β receptor 2 gene expression. These effects were blocked by suramin. Interestingly, the anti-oxidant agent superoxide dismutase (SOD) blocked TGF-β1 induced proliferation and collagen gel contraction without modulating the gene expression of α-SMA, collagen type I, TGF-β1, TGF-β R1 and TGF-β R2.

Conclusions

Our results provide evidence that targeting the TGF-β1 and PDGF pathways in human joint capsule MFs affects their contractile function. TGF-β1 may modulate MF function in the joint capsule not only via the receptor signalling pathway but also by regulating the production of profibrotic reactive oxygen species (ROS). In particular, anti-oxidant agents could offer promising options in developing strategies for the prevention and treatment of posttraumatic joint stiffness in humans.     

Amino acid racemization reveals differential protein turnover in osteoarthritic articular and meniscal cartilages

Introduction  

Certain amino acids within proteins have been reported to change from the L form to the D form over time. This process is known as racemization and is most likely to occur in long-lived low-turnover tissues such as normal cartilage. We hypothesized that diseased tissue, as found in an osteoarthritic (OA) joint, would have increased turnover reflected by a decrease in the racemized amino acid content.