Current and emerging therapeutic strategies for preventing inflammation and aggrecanase-mediated cartilage destruction in arthritis

Arthritis is a multifactorial disease for which current therapeutic intervention with high efficacy remains challenging. Arthritis predominately affects articular joints, and cartilage deterioration and inflammation are key characteristics. Current therapeutics targeting inflammatory responses often cause severe side effects in patients because of the systemic inhibition of cytokines or other global immunosuppressive activities. Furthermore, a lack of primary response or failure to sustain a response to treatment through acquired drug resistance is an ongoing concern. Nevertheless, treatments such as disease-modifying anti-rheumatic drugs, biological agents, and corticosteroids have revealed promising outcomes by decreasing pain and inflammation in patients and in some cases reducing radiographic progression of the disease. Emerging and anecdotal therapeutics with anti-inflammatory activity, alongside specific inhibitors of the A Disintegrin-like And Metalloproteinase domain with Thrombospondin-1 repeats (ADAMTS) cartilage-degrading aggrecanases, provide promising additions to current arthritis treatment strategies. Thus, it is paramount that treatment strategies be optimized to increase efficacy, reduce debilitating side effects, and improve the quality of life of patients with arthritis. Here, we review the current strategies that attempt to slow or halt the progression of osteoarthritis and rheumatoid arthritis, providing an up-to-date summary of pharmaceutical treatment strategies and side effects. Importantly, we highlight their potential to indirectly regulate ADAMTS aggrecanase activity through their targeting of inflammatory mediators, thus providing insight into a mechanism by which they might inhibit cartilage destruction to slow or halt radiographic progression of the disease. We also contrast these with anecdotal or experimental administration of statins that could equally regulate ADAMTS aggrecanase activity and are available to arthritis sufferers worldwide. Finally, we review the current literature regarding the development of synthetic inhibitors directed toward the aggrecanases ADAMTS4 and ADAMTS5, a strategy that might directly inhibit cartilage destruction and restore joint function in both rheumatoid arthritis and osteoarthritis.

Quality of life and depression among older patients waiting for joint replacement surgery

Purpose: Older patients waiting for joint replacement surgery in many western countries experience lengthy waits for their surgery. Although these patients suffer with mobility problems the nature of the disability associated with waiting for surgery is unclear. The purpose of this study was to determine health-related quality of life and symptoms of depression in persons waiting for their initial orthopaedic consultation following referral for total knee or total hip replacement surgery.

Methods: All patients who were waiting for an initial orthopaedic consultation for lower-limb joint replacement as at 25 August 2005 were surveyed. Participants were mailed questionnaires concerning demographic information, medical history, health-related quality of life (the Assessment of Quality of Life (AQoL) instrument), and symptoms of depression (Center for Epidemiologic Studies – Depression (CES-D) Scale).

Results: The 84 respondents (response rate 64%) had a mean age of 68.3 (SD 11.5 years), and 60% or respondents were women. Respondents reported an average of 1.6 (SD 0.9) medical conditions, and 85% reported osteoarthritis.} The average health-related quality of life was low (mean AQoL 0.38; SD 0.27), and near death-equivalent or worse than death-equivalent health-related quality of life (AQoL<0.1 of a maximum possible 1.0) was reported by 23% of the participants.The mean depression scale score was 16.5 (SD 11.1), and symptoms of depression (CES-D>16 of a maximum possible 60) were reported by 35% of the sample. There was a strong correlation between health-related quality of life and depression (r=–0.6).

Conclusions: Almost a third of patients waiting to see an orthopaedic surgeon about joint replacement surgery for their hip or knee had symptoms of depression. Geriatric rehabilitation services often provide interventions to these patients. The very poor quality of life reported suggests that more than exercise and strengthening will be needed to reduce disability.

Endogenous parathyroid hormone is associated with reduced cartilage volume in vivo in a population-based sample of adult women

Objectives Animal and in vitro studies suggest that parathyroid hormone (PTH) may affect articular cartilage. However, little is known of the relationship between PTH and human joints in vivo.

Design Longitudinal.

Setting Barwon Statistical Division, Victoria, Australia.

Participants 101 asymptomatic women aged 35–49 years (2007–2009) and without clinical knee osteoarthritis, selected from the population-based Geelong Osteoporosis Study.

Risk factors Blood samples obtained 10 years before (1994–1997) and stored at −80°C for random batch analyses. Serum intact PTH was quantified by chemiluminescent enzyme assay. Serum 25-hydroxyvitamin D (25(OH)D) was assayed using equilibrium radioimmunoassay. Models were adjusted for age, bone area and body mass index; further adjustment was made for 25(OH)D and calcium supplementation.

Outcome Knee cartilage volume, measured by MRI.

Results A higher lnPTH was associated with reduced medial—but not lateral—cartilage volume (regression coefficient±SD, p value: −72.2±33.6 mm3, p=0.03) after adjustment for age, body mass index and bone area. Further sinusoidal adjustment (−80.8±34.4 mm3, p=0.02) and 25(OH)D with seasonal adjustment (−72.7±35.1 mm3, p=0.04), calcium supplementation and prevalent osteophytes did not affect the results.

Conclusions A higher lnPTH might be detrimental to knee cartilage in vivo. Animal studies suggest that higher PTH concentrations reduce the healing ability of cartilage following minor injury. This may be apparent in the presence of increased loading, which occurs in the medial compartment, placing the medial cartilage at higher risk for injury.

Adaptive mechanically controlled lubrication mechanism found in articular joints

Articular cartilage is a highly efficacious water-based tribological system that is optimized to provide low friction and wear protection at both low and high loads (pressures) and sliding velocities that must last over a lifetime. Although many different lubrication mechanisms have been proposed, it is becoming increasingly apparent that the tribological performance of cartilage cannot be attributed to a single mechanism acting alone but on the synergistic action of multiple "modes" of lubrication that are adapted to provide optimum lubrication as the normal loads, shear stresses, and rates change. Hyaluronic acid (HA) is abundant in cartilage and synovial fluid and widely thought to play a principal role in joint lubrication although this role remains unclear. HA is also known to complex readily with the glycoprotein lubricin (LUB) to form a cross-linked network that has also been shown to be critical to the wear prevention mechanism of joints. Friction experiments on porcine cartilage using the surface forces apparatus, and enzymatic digestion, reveal an "adaptive" role for an HA-LUB complex whereby, under compression, nominally free HA diffusing out of the cartilage becomes mechanically, i.e., physically, trapped at the interface by the increasingly constricted collagen pore network. The mechanically trapped HA-LUB complex now acts as an effective (chemically bound) "boundary lubricant"-reducing the friction force slightly but, more importantly, eliminating wear damage to the rubbing/shearing surfaces. This paper focuses on the contribution of HA in cartilage lubrication; however, the system as a whole requires both HA and LUB to function optimally under all conditions.

Severely compromised quality of life in women and those of lower socioeconomic status waiting for joint replacement surgery

Objective
To determine health-related quality of life (HRQOL), psychological distress, physical function, and self efficacy in persons waiting for lower-limb joint replacement surgery.

Methods
A total of 214 patients on a waiting list for unilateral primary total knee or hip replacement at a large Australian public teaching hospital completed questionnaires after entry to the list. HRQOL and psychological distress were compared with available population norms.

Results
Average HRQOL was extremely poor (mean ± SD 0.39 ± 0.24) and much lower (>2 SD) than the population norm. Near death-equivalent HRQOL or worse than death-equivalent HRQOL were reported by 15% of participants. High or very high psychological distress was up to 5 times more prevalent in the waiting list sample (relative risk 5.4 for participants ages 75 years and older; 95% confidence interval 3.3, 9.0). Women had significantly lower HRQOL, self efficacy, and physical function scores than men. After adjusting for age and sex, significant socioeconomic disparities were also found. Participants who received the lowest income had the poorest HRQOL; those with the least education or the lowest income had the highest psychological distress. Low self efficacy was moderately associated with poor HRQOL (r = 0.49, P < 0.001) and more strongly associated with high psychological distress (r = -0.55, P < 0.001).

Conclusion
Patients waiting for joint replacement have very poor HRQOL and high psychological distress, especially women and those from lower socioeconomic backgrounds. Lengthy waiting lists mean patients can experience extended and potentially avoidable morbidity. Interventions to address psychological distress and self efficacy could reduce this burden and should target women and lower socioeconomic groups.

A cartilage-inspired lubrication system

Articular cartilage is an example of a highly efficacious water-based, natural lubrication system that is optimized to provide low friction and wear protection at both low and high loads and sliding velocities. One of the secrets of cartilage's superior tribology comes from a unique, multimodal lubrication strategy consisting of both a fluid pressurization mediated lubrication mechanism and a boundary lubrication mechanism supported by surface bound macromolecules. Using a reconstituted network of highly interconnected cellulose fibers and simple modification through the immobilization of polyelectrolytes, we have recreated many of the mechanical and chemical properties of cartilage and the cartilage lubrication system to produce a purely synthetic material system that exhibits some of the same lubrication mechanisms, time dependent friction response, and high wear resistance as natural cartilage tissue. Friction and wear studies demonstrate how the properties of the cellulose fiber network can be used to control and optimize the lubrication and wear resistance of the material surfaces and highlight what key features of cartilage should be duplicated in order to produce a cartilage-mimetic lubrication system.

Molecular targets in arthritis and recent trends in nanotherapy

Due to its severity and increasing epidemiology, arthritis needs no description. There are various forms of arthritis most of which are disabling, very painful, and common. In spite of breakthroughs in the field of drug discovery, there is no cure for arthritis that can eliminate the disease permanently and ease the pain. The present review focuses on some of the most successful drugs in arthritis therapy and their side effects. Potential new targets in arthritis therapy such as interleukin-1β, interleukin-17A, tumor necrosis factor alpha, osteopontin, and several others have been discussed here, which can lead to refinement of current therapeutic modalities. Mechanisms for different forms of arthritis have been discussed along with the molecules that act as potential biomarkers for arthritis. Due to the difficulty in monitoring the disease progression to detect the advanced manifestations of the diseases, drug-induced cytotoxicity, and problems with drug delivery; nanoparticle therapy has gained the attention of the researchers. The unique properties of nanoparticles make them highly attractive for the design of novel therapeutics or diagnostic agents for arthritis. The review also focuses on the recent trends in nanoformulation development used for arthritis therapy. This review is, therefore, important because it describes the relevance and need for more arthritis research, it brings forth a critical discussion of successful drugs in arthritis and analyses the key molecular targets. The review also identifies several knowledge gaps in the published research so far along with the proposal of new ideas and future directions in arthritis therapy.

Arthroscopic repair of a chondrolabral lesion associated with anterior glenohumeral dislocation

Chondrolabral lesions are uncommon after anteroinferior glenohumeral dislocations. This report describes a new dual-lesion complex that involved an avulsion of the anteroinferior glenoid labrum and a flap tear of the adjacent articular cartilage [glenoid labral tear and articular cartilage flap (GLAF) lesion]. The chondral component involved a large undermined region of the anterior half of the lower glenoid articular cartilage, and the labral component involved an avulsion from the 2.30–6 o’clock position on the glenoid. The labral tear was reconstructed with 3 suture anchors to form a neo-labrum in an attempt to overlap and stabilize the periphery of the chondral flap. A meniscal repair device was used to place a mattress stitch in the cartilage periphery to further stabilize the flap. This technique resulted in a secure repair without any chondral damage, and this remained intact on an MRI performed at a 3-month follow-up. A final 12-month follow-up showed complete recovery, as assessed by the Oxford shoulder instability score and Rowe score, and by a return to the pre-injury sporting level.

ADAMTS4 and ADAMTS5 knockout mice are protected from versican but not aggrecan or brevican proteolysis during spinal cord injury

The chondroitin sulfate proteoglycans (CSPGs) aggrecan, versican, and brevican are large aggregating extracellular matrix molecules that inhibit axonal growth of the mature central nervous system (CNS). ADAMTS proteoglycanases, including ADAMTS4 and ADAMTS5, degrade CSPGs, representing potential targets for ameliorating axonal growth-inhibition by CSPG accumulation after CNS injury. We investigated the proteolysis of CSPGs in mice homozygous for Adamts4 or Adamts5 null alleles after spinal cord injury (SCI). ADAMTS-derived 50-60 kDa aggrecan and 50 kDa brevican fragments were observed in Adamts4-/-, Adamts5-/-, and wt mice but not in the sham-operated group. By contrast Adamts4-/- and Adamts5-/- mice were both protected from versican proteolysis with an ADAMTS-generated 70 kDa versican fragment predominately observed in WT mice. ADAMTS1, ADAMTS9, and ADAMTS15 were detected by Western blot in Adamts4-/- mice' spinal cords after SCI. Immunohistochemistry showed astrocyte accumulation at the injury site. These data indicate that aggrecan and brevican proteolysis is compensated in Adamts4-/- or Adamts5-/- mice by ADAMTS proteoglycanase family members but a threshold of versican proteolysis is sensitive to the loss of a single ADAMTS proteoglycanase during SCI. We show robust ADAMTS activity after SCI and exemplify the requirement for collective proteolysis for effective CSPG clearance during SCI.

Ethical trust and social moral norms simulation : a bio-inspired agent-based modelling approach

The understanding of the micro-macro link is an urgent need in the study of social systems. The complex adaptive nature of social systems adds to the challenges of understanding social interactions and system feedback and presents substantial scope and potential for extending the frontiers of computer-based research tools such as simulations and agent-based technologies. In this project, we seek to understand key research questions concerning the interplay of ethical trust at the individual level and the development of collective social moral norms as representative sample of the bigger micro-macro link of social systems. We outline our computational model of ethical trust (CMET) informed by research findings from trust, machine ethics and neural science. Guided by the CMET architecture, we discuss key implementation ideas for the simulations of ethical trust and social moral norms.

Ageing effects on knee and ankle joint angles at key events and phases of the gait cycle.

The objective of this research was to determine whether joint angles at critical gait events and during major energy generation/absorption phases of the gait cycle would reliably discriminate age-related degeneration during unobstructed walking. The gaits of 24 healthy adults (12 young and 12 elderly) were analysed using the PEAK Motus motion analysis system. The elderly participants showed significantly greater single (60.3% versus 62.3%, p < 0.01) and double ( p < 0.05) support times, reduced knee flexion (47.7° versus 43.0°, p < 0.05) and ankle plantarflexion (16.8° compared to 3.3°, p = 0.053) at toe off, reduced knee flexion during push-off and reduced ankle dorsiflexion (16.8° compared to 22.0°, p < 0.05) during the swing phase. The plantarflexing ankle joint motion during the stance to swing phase transition (A₂) for the young group (31.3°) was about twice ( p < 0.05) that of the elderly (16.9°). Reduced knee extension range of motion suggests that the elderly favoured a flexed-knee gait to assist in weight acceptance. Reduced dorsiflexion by the elderly in the swing phase implies greater risk of toe contact with obstacles. Overall, the results suggest that joint angle measures at critical events/phases in the gait cycle provide a useful indication of age-related degeneration in the control of lower limb trajectories during unobstructed walking.

Femoral sulcus angle and increased patella facet cartilage volume in an osteoarthritic population

Objective
The patellofemoral joint is an example of an incongruent articulation commonly affected by osteoarthritis (OA). The relationship between femoral sulcus angle and the development and progression of patellofemoral OA is unclear. The aim of this study was to examine the relationship between the femoral sulcus angle at baseline and patella cartilage volume at baseline and at 2-year follow-up among community based adults with established knee OA.

Methods
One hundred subjects had magnetic resonance imaging of their symptomatic knee at baseline and at 2-year follow-up. From these images, patella cartilage volume was determined. Radiographic skyline views of the patellofemoral joint were taken at baseline to measure the femoral sulcus angle.

Results
For every 1° increase in the femoral sulcus angle (i.e., as the sulcus angle became more shallow) there was an associated 9.1 mm3 (95% CI 3.1, 15.0) increase in medial patella cartilage volume at baseline (P = 0.003). There was a similar trend that approached statistical significance between the femoral sulcus angle and the lateral patella facet cartilage volume at baseline (P = 0.09). There was no association between the femoral sulcus angle at baseline and the change in patella cartilage volume over 2 years in either patellofemoral compartment.

Conclusion
These results infer that the femoral sulcus angle is a cross-sectional determinant of the amount of patella cartilage, but is not a major determinant of the annual change of patella cartilage volume among people with knee OA. These data suggest that a shallower sulcus in the context of established OA may be an advantageous anatomical variant. Further longitudinal studies are required to determine the role of the femoral sulcus angle in OA.