PLOD2 gene expression in infrapatellar fat pad is correlated with fat mass in obese patients with end-stage knee osteoarthritis.

Objective: To investigate associations between obesity-linked systemic factors and gene expression indicative for the inflammatory and fibrotic processes in the infrapatellar fat pad (IFP), in a population of obese patients with end-stage knee osteoarthritis (KOA). Methods: We collected human IFPs from 48 patients with a mean body mass index (BMI) of 35.44 â€‹kg/m2 during total knee replacement procedures. These patients were part of a randomized controlled trial and met the criteria of having OA and a BMI of ≥30 â€‹kg/m2. Blood samples were collected to assess serum levels of glucose, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and leptin. Total body composition was measured using dual-energy X-ray absorptiometry. Gene expressions of IL6, TNFA, COL1A1, IL1B, ASMA, PLOD2 in the IFP were analyzed. Results: Univariate analysis resulted in a positive correlation between BMI and procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) expression (r2 â€‹= â€‹0.13). In univariate analyses of obesity-linked systemic factors and PLOD2, significant correlations were found for lean mass (r2 â€‹= â€‹0.20), fat mass (r2 â€‹= â€‹0.20), serum cholesterol (r2 â€‹= â€‹0.17), serum triglycerides (r2 â€‹= â€‹0.19) and serum leptin (r2 â€‹= â€‹0.10). A multiple linear regression model indicated fat mass to be a strong predictor of PLOD2 production in the IFP (r2 â€‹= â€‹0.22, P â€‹= â€‹0.003). Conclusion: Our study demonstrates the positive association between fat mass and PLOD2 expression in the IFP of obese end-stage knee OA patients. This may indicate that within this patient population the fibrotic process in the IFP is influenced by systemic adipose tissue, next to local inflammatory processes.

Three-dimensional displacement after a medializing calcaneal osteotomy in relation to the osteotomy angle and hindfoot alignment.

BACKGROUND: A medializing calcaneal osteotomy is frequently performed to correct adult-acquired flatfoot deformities, but there is lack of data on the associated three-dimensional variables defining the final correction. The aim of this study was to assess the correlation between the pre-operative hindfoot valgus deformity and calcaneal osteotomy angles and the post-operative calcaneal displacement. METHODS: Weight-bearing CT scans obtained pre- and post-operatively were retrospectively analyzed for sixteen patients. Corresponding three-dimensional bone models were used to measure valgus deformity pre- and post-operatively, inclination of the osteotomy and displacement of the calcaneus. Linear regression was conducted to assess the relationship between these measurements. RESULTS: On average, the hindfoot valgus changed from 13.1° (±4.6) pre-operatively to 5.7° (±4.3) post-operatively. A mean inferior displacement of 3.2mm (±1.3) was observed along the osteotomy with a mean inclination of 54.6° (±5.6), 80.5° (±10.7), -13.7° (±15.7) in the axial, sagittal and coronal planes, respectively. A statistically significant positive relationship (p<.05, R2=0.6) was found between the pre-operative valgus, the axial osteotomy inclination, and the inferior displacement. CONCLUSIONS: This study shows that the degree of pre-operative hindfoot valgus and the axial osteotomy angle are predictive factors for the amount of post-operative inferior displacement of the calcaneus. These findings demonstrate the added value of a computer-based pre-operative planning in clinical practice. Level of evidence II Prospective comparative study.

Weightbearing CT in normal hindfoot alignment - Presence of a constitutional valgus?

BACKGROUND: The normal hindfoot angle is estimated between 2° and 6° of valgus in the general population. These results are solely based on clinical findings and plain radiographs. The purpose of this study is to assess the hindfoot alignment using weightbear CT. METHODS: Forty-eight patients, mean age of 39.6±13.2 years, with clinical and radiological absence of hindfoot pathology were included. A weightbear CT was obtained and allowed to measure the anatomical tibia axis (TAx) and the hindfoot alignment (HA). The HA was firstly determined using the inferior point of the calcaneus (HAIC). A density measurement of this area was subsequently performed to analyze if this point concurred with an increased ossification, indicating a higher load exposure. Secondly the HA was determined by dividing the calcaneus in the long axial view (HALA) and compared to the (HAIC) to point out any possible differences attributed to the measurement method. Reliability was assessed using an intra class correlation coefficient (ICC). RESULTS: The mean HAIC equaled 0.79° of valgus±3.2 (ICCHA IC=0.73) with a mean TAx of 2.7° varus±2.1 (ICCTA=0.76). The HALA equaled 9.1° of valgus±4.8 (ICCHA LA=0.71) and differed significantly by a P<0.001 from the HAIC, which showed a more neutral alignment. Correlation between both was shown to be good by a Spearman's correlation coefficient of 0.74. The mean density of the inferior calcaneal area equaled 271.3±84.1 and was significantly higher than the regional calcaneal area (P<0.001). CONCLUSIONS: These results show a more neutral alignment of the hindfoot in this group of non-symptomatic feet as opposed to the generally accepted constitutional valgus. This could have repercussion on hindfoot position during fusion or in quantifying the correction of a malalignment. The inferior calcaneus point in this can be used during pre-operative planning of a hindfoot correction as an anatomical landmark due to its shown influence on load transfer.

Transportal femoral drilling creates more horizontal ACL graft orientation compared to transtibial drilling: A 3D CT imaging study.

BACKGROUND: The principle of anatomic anterior cruciate ligament (ACL) reconstruction is to create a femoral and tibial tunnel that resembles the insertion of the native ACL. Anatomic reconstruction leads to a more horizontal graft orientation that provides more rotational stability. The aim of this study is to investigate the best method to achieve anatomical reconstruction of femoral insertion of the ACL and thus, a more horizontal orientation of the ACL. We compared tunnel position and orientation between transportal femoral drilling technique and transtibial technique. METHODS: Thirty-two patients were included. Post-operative CT scans were obtained and femur, tibia and ACL tunnels were reconstructed. The position and orientation of tibial and femoral tunnels were quantified using the quadrant method, and femoral tunnel length, ellipticity and posterior wall breakage were assessed. We also investigated clinical outcome. RESULTS: Analyses show that transportal drilled femoral tunnels were situated significantly lower than transtibial drilled tunnels (p<0.0001), resulting in a significantly more horizontal oriented ACL in the transportal group in coronal (p<0.0001) and sagittal plane (p=0.01). No differences were observed in depth of femoral tunnel position (p=0.44). Femoral tunnel length was shorter in the transportal group (p=0.01) with a more ellipsoidal femoral aperture (p=0.01). There were no differences between both groups in tibial position. There were no differences in clinical outcome measure between the transportal and transtibial groups. CONCLUSION: This study indicates that transportal drilling of the femoral tunnel leads to a more horizontal graft orientation of the ACL, without differences in clinical outcome.

The infrapatellar fat pad from diseased joints inhibits chondrogenesis of mesenchymal stem cells.

Cartilage repair by bone marrow derived mesenchymal stem cells (MSCs) can be influenced by inflammation in the knee. Next to synovium, the infrapatellar fat pad (IPFP) has been described as a source for inflammatory factors. Here, we investigated whether factors secreted by the IPFP affect chondrogenesis of MSCs and whether this is influenced by different joint pathologies or obesity. Furthermore, we examined the role of IPFP resident macrophages. First, we made conditioned medium from IPFP obtained from osteoarthritic joints, IPFP from traumatically injured joints during anterior cruciate ligament reconstruction, and subcutaneous adipose tissue. Additionally, we made conditioned medium of macrophages isolated from osteoarthritic IPFP and of polarised monocytes from peripheral blood. We evaluated the effect of different types of conditioned medium on MSC chondrogenesis. Conditioned medium from IPFP decreased collagen 2 and aggrecan gene expression as well as thionin and collagen type 2 staining. This anti-chondrogenic effect was the same for conditioned medium from IPFP of osteoarthritic and traumatically injured joints. Furthermore, IPFP from obese (Body Mass Index >30) donors did not inhibit chondrogenesis more than that of lean (Body Mass Index <25) donors. Finally, conditioned medium from macrophages isolated from IPFP decreased the expression of hyaline cartilage genes, as did peripheral blood monocytes stimulated with pro-inflammatory cytokines. The IPFP and the resident pro-inflammatory macrophages could therefore be targets for therapies to improve MSC-based cartilage repair.

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.

Does infrapatellar fat pad resection in total knee arthroplasty impair clinical outcome? A systematic review.

INTRODUCTION: The infrapatellar fat pad (IPFP) is often removed during total knee arthroplasty (TKA). No evidence based guidelines on changes in clinical outcome have yet been described. The aim of this review is to investigate whether regular removal of the IPFP during TKA should be performed. MATERIAL AND METHODS: Seven databases were systematically searched. Clinical studies, in which TKA with IPFP resection was compared with IPFP preservation, were included. Risk of bias was assessed using the Cochrane collaboration tool. Studies reporting anterior knee pain, patellar tendon length, range of motion, patellar vascularisation or functional outcome were included. RESULTS: The indication for TKA varied in the different studies: osteoarthritis (OA), rheumatic arthritis (RA) and multiple indications (OA, RA and osteonecrosis). After IPFP resection: 1. For OA, no differences in function, range of motion, and anterior knee pain were found. 2. In the RA study, there was a trend towards more discomfort and a decrease in function. 3. In OA and RA patients a decrease in patellar tendon length was observed. 4. One study reported no decrease in patellar vascularisation. DISCUSSION: Limitations of this review are the high risk of bias scores of the included studies, the varying outcome measures, follow up, number and type of participants. Randomised clinical trials are required to support or refute the results, contributing to a possible future evidence based guideline on IPFP resection during TKA.

Monounsaturated and Saturated, but Not n-6 Polyunsaturated Fatty Acids Decrease Cartilage Destruction under Inflammatory Conditions: A Preliminary Study.

PURPOSE: Osteoarthritis (OA) is associated with obesity in which altered fatty acid levels have been observed. We investigated whether the most common fatty acids in synovial fluid influence cartilage deterioration in OA. DESIGN: Cartilage was obtained from OA patients undergoing total knee arthroplasty. Chondrocytes or cartilage explants were cultured with linoleic (n-6 polyunsaturated), oleic (monounsaturated), or palmitic (saturated) acid. After preculture, media were renewed and inflammation was simulated in half of the samples by addition of 10 ng/mL tumor necrosis factor-α (TNFα) with or without the fatty acids. Effects on lipid uptake (Oil-Red-O), cell toxicity (lactate dehydrogenase), prostaglandin-E2 (PGE2) release and gene expression for prostaglandin-endoperoxide synthase-2 (PTGS2), matrix metalloproteinase-1 (MMP1), and MMP13, and a disintegrin and metalloproteinase with thrombospondin motifs 4 were determined on chondrocytes in monolayer. Effects on glycosaminoglycan (GAG) release were evaluated on cartilage explants. RESULTS: None of the fatty acids were cytotoxic and all were taken up by the cells, resulting in a higher amount of intracellular lipid in chondrocytes. Linoleic acid increased PGE2 production in the presence of TNFα. Oleic acid and palmitic acid inhibited MMP1 gene expression in chondrocytes stimulated with TNFα. In cartilage explants, GAG release was also inhibited by oleic acid and palmitic acid, and oleic acid decreased PTGS2 gene expression in stimulated chondrocytes. CONCLUSIONS: Linoleic acid has a pro-inflammatory effect on cartilage whereas oleic acid and palmitic acid seem to inhibit cartilage destruction. These results indicate that altered fatty acid levels may influence loss of cartilage structure in OA.

Statin use is associated with reduced incidence and progression of knee osteoarthritis in the Rotterdam study.

BACKGROUND: Osteoarthritis is the most frequent chronic joint disease causing pain and disability. Besides biomechanical mechanisms, the pathogenesis of osteoarthritis may involve inflammation, vascular alterations and dysregulation of lipid metabolism. As statins are able to modulate many of these processes, this study examines whether statin use is associated with a decreased incidence and/or progression of osteoarthritis. METHODS: Participants in a prospective population-based cohort study aged 55 years and older (n=2921) were included. x-Rays of the knee/hip were obtained at baseline and after on average 6.5 years, and scored using the Kellgren and Lawrence score for osteoarthritis. Any increase in score was defined as overall progression (incidence and progression). Data on covariables were collected at baseline. Information on statin use during follow-up was obtained from computerised pharmacy databases. The overall progression of osteoarthritis was compared between users and non-users of statins. Using a multivariate logistic regression model with generalised estimating equation, OR and 95% CI were calculated after adjusting for confounding variables. RESULTS: Overall progression of knee and hip osteoarthritis occurred in 6.9% and 4.7% of cases, respectively. The adjusted OR for overall progression of knee osteoarthritis in statin users was 0.43 (95% CI 0.25 to 0.77, p=0.01). The use of statins was not associated with overall progression of hip osteoarthritis. CONCLUSIONS: Statin use is associated with more than a 50% reduction in overall progression of osteoarthritis of the knee, but not of the hip.

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.

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)1ß 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 IL1ß, 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 IL1ß. 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).

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.

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.