S. Clockaerts

The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review

INTRODUCTION Osteoarthritis (OA) of the knee joint is caused by genetic and hormonal factors and by inflammation, in combination with biomechanical alterations. It is characterized by loss of articular cartilage, synovial inflammation and subchondral bone sclerosis. Considerable evidence indicates that the menisci, ligaments, periarticular muscles and the joint capsule are also involved in the OA process. This paper will outline the theoretical framework for investigating the infrapatellar fat pad (IPFP) as an additional joint tissue involved in the development and progression of knee-OA. METHODS A literature search was performed in Pubmed from 1948 until October 2009 with keywords InFrapatellar fat pad, Hoffa fat pad, intraarticular adipose tissue, knee, cartilage, bone, cytokine, adipokine, inflammation, growth factor, arthritis, and OA. RESULTS The IPFP is situated intracapsularly and extrasynovially in the knee joint. Besides adipocytes, the IPFP from patients with knee-OA contains macrophages, lymphocytes and granulocytes, which are able to contribute to the disease process of knee-OA. Furthermore, the IPFP contains nociceptive nerve fibers that could in part be responsible for anterior pain in knee-OA. These nerve fibers secrete substance P, which is able to induce inflammatory responses and cause vasodilation, which may lead to IPFP edema and extravasation of the immune cells. The IPFP secretes cytokines, interleukins, growth factors and adipokines that influence cartilage by upregulating the production of matrix metalloproteinases (MMPs), stimulating the expression of pro-inflammatory cytokines and inhibiting the production of cartilage matrix proteins. They may also stimulate the production of pro-inflammatory mediators, growth factors and MMPs in synovium. CONCLUSION These data are consistent with the hypothesis that the IPFP is an osteoarthritic joint tissue capable of modulating inflammatory and destructive responses in knee-OA.

Osteoarthritis Induction Leads to Early and Temporal Subchondral Plate Porosity in the Tibial Plateau of Mice An In Vivo Microfocal Computed Tomography Study

OBJECTIVE In osteoarthritis (OA), changes occur in both cartilage and subchondral bone. The subchondral bone plate facilitates normal cross-talk between articular cartilage and trabecular subchondral bone, and adaptive changes in the plate due to OA may therefore disturb cross-talk homeostasis. To investigate these changes over time, we examined the cartilage-subchondral bone interface using a combined approach of histologic analysis and in vivo microfocal computed tomography. METHODS Sixteen-week-old male C57BL/6 mice (n=32) received intraarticular injections of collagenase in 1 joint to induce instability-related OA and received saline injections in the contralateral knee joint (control joint). At 2, 4, 6, 10, and 14 weeks after injection, changes in the tibial subchondral bone plate and subchondral trabeculae were analyzed. RESULTS Two weeks after injection, collagenase-injected joints had significantly more cartilage damage and osteophytosis than did control joints. Osteoclast activity directly underneath the subchondral bone plate was significantly elevated in collagenase-injected joints compared to control joints (mean±SEM osteoclast surface/bone surface 11.07±0.79% versus 7.60±0.81%), causing the plate to become thinner and creating a large increase in subchondral bone plate porosity (mean±SEM cumulative porosity volume 0.05±0.04×10(-3) mm3 in control joints versus 2.52±0.69×10(-3) mm3 in collagenase-injected joints). Four weeks after injection, the previously formed perforations disappeared, coinciding with a significant rise in osteoblast activity in the subchondral trabecular bone in collagenase-injected joints compared to control joints (mean ± SEM bone formation rate/bone surface 0.62±0.13 μm3/μm2 per day versus 0.30±0.03 μm3/μm2 per day). CONCLUSION The current study is the first to provide quantitative longitudinal data on the dynamic changes in the subchondral bone plate after OA induction. The development of plate perforations may enhance mutual interaction between subchondral trabeculae, bone marrow cells, and the articular cartilage in OA.

ADAMTS5−/− mice have less subchondral bone changes after induction of osteoarthritis through surgical instability: implications for a link between cartilage and subchondral bone changes

OBJECTIVE Osteoarthritis (OA) is characterized by damaged articular cartilage and changes in subchondral bone. Previous work demonstrated aggrecanase-2 deficient (ADAMTS5-/-) mice to be protected from cartilage damage induced by joint instability. This study analyzed whether this protective effect on cartilage is also reflected in the subchondral bone structure. METHODS Right knee joints from 10-week old male wild type (WT) and ADAMTS5-/- mice received transection of the medial meniscotibial ligament to induce OA, whereas left knees were left unoperated. After 8 weeks knee joints were scanned by micro-CT. The proximal tibia was selected for further analysis. Histology was performed to evaluate cartilage damage and osteoclast presence. RESULTS ADAMTS5-/- joints had a significantly thinner subchondral plate and less epiphyseal trabecular bone compared to WT joints. Histology confirmed previous findings that ADAMTS5-/- mice have significantly less cartilage damage than WT in the instability-induced OA model. Although the subchondral bone plate became significantly thicker at the medial tibial plateau in operated joints of both genotypes, the percentage increase was significantly smaller in ADAMTS5-/- mice (WT: 20.7+/-4.7%, ADAMTS5-/-: 8.3+/-1.2% compared to the left unoperated control joint). In ADAMTS5-/- animals a significant decrease was found in both Oc.N./BS and Oc.S./BS. Finally, in WT but not in ADAMTS5-/- mice a significant correlation was found between medial subchondral bone plate thickness and cartilage damage at the medial tibial plateau. CONCLUSION ADAMTS5-/- joints that were protected from cartilage damage showed minor changes in the subchondral bone structure, in contrast to WT mice where substantial changes were found. This finding suggests links between the process of cartilage damage and subchondral bone changes in instability-induced OA.

A systematic review on changed biomechanics of lower extremities in obese individuals: A possible role in development of osteoarthritis

Obesity has been identified as a risk factor for osteoarthritis. For the weight‐bearing joints, the combination of increased load and changed joint biomechanics could be regarded as underlying principle for this relation. This systematic review of the literature focused on the differences between obese and normal‐weight subjects in biomechanics of the hip, knee and ankle joint during every day movements to summarize differences in joint load due to both higher body weight and differences in movement patterns. A systematic search, up to November 2010, was performed in the Pubmed and Embase databases. This review showed that obese individuals adjust their movement strategy of every day movements. At self‐selected speed, obese individuals walked slower, with shorter and wider steps, had longer stance duration and had a greater toe‐out angle compared with normal‐weight individuals. Obese sit‐to‐stand movement was characterized by less hip flexion and greater foot displacement. Obese individuals showed altered biomechanics during every day movements. These altered biomechanics could be related to the initiation of osteoarthritis by a change in the load‐bearing regions of the articular cartilage in the weight‐bearing joints.

Association of atherosclerosis with presence and progression of osteoarthritis: the Rotterdam Study

Objective This study examined whether vascular alterations are associated with the presence and progression of osteoarthritis of the knee, the hip and the different hand joints in a large prospective cohort study. Methods In this population-based study involving participants aged 55 years and older (Rotterdam Study I), men (n=2372) and women (n=3278) were analysed separately. x-Rays of the knee, hip and hand were scored using the Kellgren and Lawrence score for osteoarthritis at baseline, after 6.6 years and 10 years. Measures of atherosclerosis (carotid intima media thickness (IMT) and carotid plaque) and data on covariates (age, body mass index, hypertension, cholesterol ratio, diabetes mellitus and smoking) were collected at baseline. Multivariate logistic regression models with generalised estimated equations were used to calculate OR and corresponding 95% CI. Secondary multiple comparison adjustment resulted in a significance level of p<0.0021. Results In women, IMT showed an independent association with the prevalence of knee osteoarthritis (adjusted OR (aOR) 1.7, 1.1 to 2.7), and carotid plaque with distal interphalangeal (DIP) osteoarthritis (aOR 1.4, 1.2 to 1.7) and with metacarpophalangeal osteoarthritis (aOR 1.5, 1.1 to 2.2). An independent association for IMT with progression of metacarpophalangeal osteoarthritis was found in women (aOR 2.9, 1.18 to 6.93). Additional adjustment for multiple testing yielded a significant association between carotid plaque and DIP osteoarthritis in women (p<0.001). Conclusions This study showed independent associations of atherosclerosis with osteoarthritis of the knee and hand joints in women. The evidence was most solid for a relation with DIP osteoarthritis. More research is needed to confirm the associations and examine the differential association with various joints.

Peroxisome proliferator activated receptor alpha activation decreases inflammatory and destructive responses in osteoarthritic cartilage

OBJECTIVE Peroxisome proliferator activated receptor α (PPARα) agonists are used in clinical practice as lipid-lowering drugs and are also known to exert anti-inflammatory effects on various tissues. We hypothesized that PPARα activation leads to anti-inflammatory and anti-destructive effects in human OA cartilage. METHODS Cartilage explants obtained from six OA patients were cultured for 48 h with 10 ng/ml interleukin (IL)1β as a pro-inflammatory stimulus. 100 μM Wy-14643, a potent and selective PPARα agonist, was added to the cultures and gene expression of matrix metalloproteinase (MMP)1, MMP3, MMP13, collagen type II (COL2A1), aggrecan and PPARα in cartilage explants and the release of glycosaminoglycans (GAGs), nitric oxide (NO) and prostaglandin E(2) (PGE(2)) in the culture media were analyzed and compared to the control without Wy-14643. RESULTS Addition of Wy-14643 decreased mRNA expression of MMP1, MMP3 and MMP13 in cartilage explants that responded to IL1β, whereas Wy-14643 did not affect gene expression of COL2A1 and aggrecan. Wy-14643 also decreased secretion of inflammatory marker NO in the culture medium of cartilage explants responding to IL1β. Wy-14643 inhibited the release of GAGs by cartilage explants in culture media. CONCLUSION PPARα agonist Wy-14643 inhibited the inflammatory and destructive responses in human OA cartilage explants and did not have an effect on COL2A1 or aggrecan mRNA expression. These effects of PPARα agonists on osteoarthritic cartilage warrant further investigation of these drugs as a potential therapeutic strategy for osteoarthritis (OA).

Comment on ‘Associations between statin use and changes in pain, function and structural progression: a longitudinal study of persons with knee osteoarthritis’

We read with interest the article by Riddle et al 1 entitled ‘Associations between Statin use and changes in pain, function and structural progression: a longitudinal study of persons with knee osteoarthritis’, where the authors used data on a subset of 2207 subjects included in the Osteoarthritis Initiative with radiological suspected or confirmed knee osteoarthritis (OA). Their article was partly based on the article by Clockaerts et al ,2 where we report an association between statin use, and incidence and progression of radiological knee OA in the Ommoord cohort of the Rotterdam study. Riddle et al also investigated the association between pain and function scores, progression of radiological knee OA and statin use, and found no associations. Their data may indicate that there is indeed no association between statin use and knee OA, and that our results were due to an unexpected bias or …

TruFit plug for repair of osteochondral defects: where is the evidence? : systematic review of literature

Objective: Treatment of osteochondral defects remains a challenge in orthopedic surgery. The TruFit plug has been investigated as a potential treatment method for osteochondral defects. This is a biphasic scaffold designed to stimulate cartilage and subchondral bone formation. The aim of this study is to investigate clinical, radiological, and histological efficacy of the TruFit plug in restoring osteochondral defects in the joint. Design: We performed a systematic search in five databases for clinical trials in which patients were treated with a TruFit plug for osteochondral defects. Studies had to report clinical, radiological, or histological outcome data. Quality of the included studies was assessed. Results: Five studies describe clinical results, all indicating improvement at follow-up of 12 months compared to preoperative status. However, two studies reporting longer follow-up show deterioration of early improvement. Radiological evaluation indicates favorable MRI findings regarding filling of the defect and incorporation with adjacent cartilage at 24 months follow-up, but conflicting evidence exists on the properties of the newly formed overlying cartilage surface. None of the included studies showed evidence for bone ingrowth. The few histological data available confirmed these results. Conclusion: There are no data available that support superiority or equality of TruFit compared to conservative treatment or mosaicplasty/microfracture. Further investigation is needed to improve synthetic biphasic implants as therapy for osteochondral lesions. Randomized controlled clinical trials comparing TruFit plugs with an established treatment method are needed before further clinical use can be supported.

Statins and fibrates do not affect development of spontaneous cartilage damage in STR/Ort mice

OBJECTIVE Since statins and fibrates are capable of improving the metabolic profile of patients as well as decreasing inflammation, they are considered as potential drugs for preventing osteoarthritis (OA). The goal of the present study was to investigate the effect of these drugs in the STR/Ort spontaneous OA mouse model. DESIGN Male STR/Ort mice received control diet or control diet containing two different dosages of simvastatin or fenofibrate or a combination of both. Mice were euthanized after 16 weeks of treatment at the age of 24 weeks. Serum analysis for metabolic and inflammatory markers, histologic OA grading and micro computed tomography (μCT) analysis of subchondral bone plate were performed. RESULTS Simvastatin treatment did not have a statistically significant effect on any of the measured parameters. Fenofibrate treated mice gained less body weight (BW) and had lower serum amyloid A (SAA) levels, but higher Interleukin (IL)-1α and MIP1α than other mice. Mice treated with 200 mg/kg BW/day fenofibrate had less subchondral bone plate volume than control, but no statistically significant reduction in cartilage damage. In the combination treatment group, BW and SAA were lower than control. Overall, bodyweight, synovium membrane cell layers and SAA levels correlated to subchondral bone plate changes and subchondral bone plate changes correlated to cartilage damage. CONCLUSIONS Statins and fibrates did not affect development of cartilage damage in the STR/Ort spontaneous OA mouse model. Fenofibrates however, had an effect on BW, serum inflammation markers and subchondral bone plate morphology.

Fibrates as therapy for osteoarthritis and rheumatoid arthritis? A systematic review

Fibrates are used as lipid-lowering drugs to prevent cardiovascular pathology. Fibrates are ligands of peroxisome proliferator-activated receptor α (PPARα). Besides altering lipid metabolism, PPARα ligands exert anti-inflammatory effects on various cell types. In this study, we hypothesized that PPARα agonists exert beneficial effects on osteoarthritis (OA) and rheumatoid arthritis (RA) by their local anti-inflammatory effects, but also by their systemic influences. A systematic literature search of Medline and EMBASE databases was performed up to August 2011. The main search items were osteoarthritis, rheumatoid arthritis, peroxisome proliferator-activated receptor alpha and fibrates. Inclusion criteria were in vivo or in vitro studies regarding humans or animals in which the effects of PPARα ligands were studied. Six in vivo human studies, four in vivo animal studies and seven in vitro studies were included. The in vivo human studies showed all beneficial clinical effects of PPARα ligands, but studies were small and only four were randomized. Ligands for PPARα significantly reduced pain, swelling of the joints and decreased systemic inflammatory markers. In vitro and in vivo animal studies indicate that PPARα agonists inhibit bone resorption, and reduce inflammatory and destructive responses in cartilage and synovium. PPARα agonists such as fibrates should be considered as potential therapeutic strategy for RA. There is no clinical evidence for their use in OA, although in vitro studies indicate that PPARα agonists demonstrate different joint-protective effects locally, and systemic effects on inflammation, serum lipid levels and vascular pathology. Animal studies should be performed and after confirmation of the protective effects of PPARα, large randomized controlled trials could investigate fibrates in OA and RA.