Infrapatellar fat pad induces an inflammatory and catabolic phenotype on autologous fibroblast-like synoviocytes from severe knee oa patients

Background:One of the hurdles in osteoarthritis (OA) drug discovery and the improvement of therapeutic approaches is the early identification of patients who will progress. It is therefore crucial to find efficient and reliable means of screening OA progressors. Although the main risk factors, age, gender and body mass index (BMI), are important, they alone are poor predictors. However, serum factors could be potential biomarkers for early prediction of knee OA progression.Objectives:In a first step toward finding early reliable predictors of OA progressors, this study aimed to determine, in OA individuals, the optimum combination of serum levels of adipokines/related inflammatory factors, their ratios, and the three main OA risk factors for predicting knee OA infrapatellar fat pad (IPFP) volume, as this tissue has been associated with knee OA onset and progression.Methods:Serum and magnetic resonance images (MRI) were from the Osteoarthritis Initiative at baseline. Variables (48) comprised the 3 main OA risk factors (age, gender, BMI), 6 adipokines, 3 inflammatory factors, and their 36 ratios. IPFP volume was assessed on MRI with a neural network methodology. The best variables and models were identified in Total cohort (n=678), High-BMI (n=341) and Low-BMI (n=337), using an artificial intelligence selection approach: the adaptive neuro-fuzzy inference system embedded with fuzzy c-means clustering (ANFIS-FCM). Performance was validated using uncertainty analyses and statistical indices. Reproducibility was done using 80 OA patients from a clinical trial (female, n=57; male, n=23).Results:For the three groups, 8.44E+14 sub-variables were investigated and 48 models were selected. The best model for each group included five variables: the three risk factors and adipsin/C-reactive protein combined for Total cohort, adipsin/chemerin; High-BMI, chemerin/adiponectin high molecular weight; and Low-BMI, interleukin-8. Data also revealed that the main form of the ratio used for the model was justified, as the use of the inverse form slightly decreased the performance of the model in both training and testing stages. Further investigation indicated that gender improved (13-16%) the prediction results compared to the BMI-based models. For each gender, we then generated a pseudocode (an evolutionary computation equation) with the 5 variables for predicting IPFP volume. Reproducibility experiments were excellent (correlation coefficient: female 0.83, male 0.95).Conclusion:This study demonstrates, for the first time, that the combination of the serum levels of adipokines/inflammatory factors and the three main risk factors of OA could predict IPFP volume with high reproducibility, and superior performance with gender separation. By using the models for each gender and the pseudocodes for OA patients provided in this study, the next step will be to develop a predictive model for OA progressors.Acknowledgments:This work was funded by the Chair in Osteoarthritis of the University of Montreal, the Osteoarthritis Research Unit of the University of Montreal Hospital Research Centre, the Groupe de recherches des maladies rhumatismales du Québec and by ArthroLab Inc., all from Montreal, Quebec, Canada.Disclosure of Interests:Hossein Bonakdari: None declared, Ginette Tardif: None declared, François Abram Employee of: ArthroLab Inc., Jean-Pierre Pelletier Shareholder of: ArthroLab Inc., Grant/research support from: TRB Chemedica, Speakers bureau: TRB Chemedica and Mylan, Johanne Martel-Pelletier Shareholder of: ArthroLab Inc., Grant/research support from: TRB Chemedica

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Effects of Conditioned Medium From Osteoarthritic Cartilage Fragments on Donor-Matched Infrapatellar Fat Pad–Derived Mesenchymal Stromal Cells

The American Journal of Sports Medicine ◽

10.1177/0363546519869241 ◽

2019 ◽

Vol 47 (12) ◽

pp. 2927-2936 ◽

Cited By ~ 1

Author(s):

Zhenlan Fu ◽

Xiongbo Song ◽

Lin Guo ◽

Liu Yang ◽

Cheng Chen

Keyword(s):

Conditioned Medium ◽

Chondrogenic Differentiation ◽

Infrapatellar Fat Pad ◽

Control Medium ◽

Fat Pad ◽

Negative Effects ◽

Osteoarthritic Cartilage ◽

Chondrogenic Medium ◽

Knee Oa

Background: Mesenchymal stromal cell (MSC)–based therapies have emerged as a promising strategy for osteoarthritis (OA) treatment. In particular, infrapatellar fat pad (IPFP)–derived MSCs have become a good option to treat knee OA. Purpose: To investigate the influence of the local microenvironment of the knee joint, especially OA cartilage, on the bioactivities of injected/implanted IPFP MSCs. Study Design: Controlled laboratory study. Methods: Conditioned medium (CM) derived from OA cartilage fragments was collected and characterized. Donor-matched IPFP MSCs were treated with control medium (Dulbecco’s modified Eagle medium (DMEM)/F-12 or chondrogenic medium), control medium + CM, or CM alone; and a series of behaviors including the viability, migration, chondrogenic and hypertrophic differentiation, and catabolic activity of IPFP MSCs were evaluated among groups. Results: There were 14 cytokines detected in CM. CM treatment improved the viability of IPFP MSCs. CM hindered the migration of IPFP MSCs. In chondrogenic differentiation, the presence of CM increased the expression of chondrogenic markers but also enhanced the state of hypertrophy and catabolism. Conclusion: OA cartilage–secreted factors could induce chondrogenic differentiation but also resulted in negative effects including the weakened migration, increased hypertrophy, and catabolism of IPFP MSCs in vitro. Clinical Relevance: These findings provide an insight on the fate of IPFP MSCs after intra-articular injections.

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Association Between Infrapatellar Fat Pad Volume and Knee Structural Changes in Patients with Knee Osteoarthritis

The Journal of Rheumatology ◽

10.3899/jrheum.150175 ◽

2015 ◽

Vol 42 (10) ◽

pp. 1878-1884 ◽

Cited By ~ 40

Author(s):

Jingyu Cai ◽

Jianhua Xu ◽

Kang Wang ◽

Shuang Zheng ◽

Fan He ◽

...

Keyword(s):

Knee Osteoarthritis ◽

Structural Changes ◽

Spin Echo ◽

Cartilage Volume ◽

Infrapatellar Fat Pad ◽

Fast Spin Echo ◽

Cartilage Defects ◽

Fat Pad ◽

Cross Sectional ◽

Knee Oa

Objective.The function of the infrapatellar fat pad (IPFP) in knee osteoarthritis (OA) remains uncertain. This study aimed to examine cross-sectional associations between IPFP volume and knee structures in patients with knee OA.Methods.The study included 174 patients with clinical knee OA (mean age, 55.5 yrs). Fat-suppressed 3-D T1-weighted spoiled gradient recall magnetic resonance imaging (MRI) was used to measure the IPFP and cartilage volume. T2-weighted fast spin echo MRI was used to assess cartilage defects and bone marrow lesions (BML). Radiographic knee osteophytes and joint space narrowing (JSN) were assessed using the Osteoarthritis Research Society International atlas.Results.After adjustment for potential confounders, greater IPFP volume was associated with greater tibial and patellar cartilage volume (all p < 0.05), and fewer cartilage defects at all sites (OR 0.88–0.91, all p < 0.05). IPFP volume was associated with presence of BML at lateral tibial and medial femoral sites (OR 0.88–0.91, all p < 0.05) and osteophytes at lateral tibiofemoral compartment (OR 0.88, p < 0.05). IPFP volume was not significantly associated with JSN.Conclusion.Greater IPFP volume was associated with greater knee cartilage volume and fewer structural abnormalities, suggesting a protective role of IPFP size in knee OA.

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Infrapatellar fat pad area on knee MRI: does it correlate with the extent of knee osteoarthritis?

Egyptian Journal of Radiology and Nuclear Medicine ◽

10.1186/s43055-020-00383-z ◽

2021 ◽

Vol 52 (1) ◽

Author(s):

Eman Ragab ◽

Dena Serag

Keyword(s):

Large Scale ◽

Cartilage Damage ◽

Surrogate Marker ◽

Joint Space ◽

Protective Role ◽

Infrapatellar Fat Pad ◽

Cartilage Defects ◽

Fat Pad ◽

Knee Oa ◽

Maximal Area

Abstract Background Osteoarthritis (OA) of the knee joint is a common cause of chronic disability in older adults. During the past 10 years, the infrapatellar fat pad (IPFP) has emerged as a new player in the pathogenesis of knee OA. Its exact role in the pathogenesis of knee OA remains uncertain. While many studies focused on the detrimental effect of the chemical mediators released by IPFP and their role in the accentuation of the development of OA, only few studies elucidated the beneficial effect of IPFP maximal area as a local shock absorber protecting the adjacent articular structures from progressive damage. The aim of this study was to evaluate the relation between the IPFP maximal area and the prevalence of OA manifestations. We also studied the relation between the subcutaneous (SC) fat thicknesses on the medial aspect of the knee as a surrogate marker of body obesity and the IPFP area. Results A total of 216 knee scans for 188 adult patients (64 males and 124 females) who met the inclusion criteria were examined. They were between 45 and 66 years (mean 52.5 years). The mean IPFP area for all patients was 6.9 cm2 (± 1.6 SD) (ranged from 4.5 to 11 cm2). After adjustment for potential confounders, there was a significant negative association between IPFP area and radiographic manifestations of OA (osteophites, joint space narrowing, and grade of OA) (P value < 0.001 for each), as well as MRI manifestations of OA (cartilage defects and subchondral bone marrow lesions) (P value < 0.001 and < 0.003, respectively). There was a negative but non-significant association between IPFP area and SC fat thickness. Conclusion In our study, we found supportive evidence that IPFP maximal area is associated with fewer osteoarthritic knee changes and less cartilage damage, suggesting that it plays a protective role against the development and progression of OA. Further large-scale clinical studies are awaited to confirm the obtained results. Based on our findings, it would be recommended to avoid IPFP resection during surgery in order to maintain its protective effect.

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Cross-sectional and longitudinal associations between signal intensity alterations in infrapatellar fat pad and knee structural changes in patients with symptomatic knee OA

Osteoarthritis and Cartilage ◽

10.1016/j.joca.2016.01.764 ◽

2016 ◽

Vol 24 ◽

pp. S424

Author(s):

W. Han ◽

D. Aitken ◽

Z. Chen ◽

X. Jin ◽

X. Wang ◽

...

Keyword(s):

Signal Intensity ◽

Structural Changes ◽

Infrapatellar Fat Pad ◽

Fat Pad ◽

Cross Sectional ◽

Knee Oa ◽

Symptomatic Knee ◽

Longitudinal Associations

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Contribution of Infrapatellar Fat Pad and Synovial Membrane to Knee Osteoarthritis Pain

BioMed Research International ◽

10.1155/2019/6390182 ◽

2019 ◽

Vol 2019 ◽

pp. 1-18 ◽

Cited By ~ 21

Author(s):

Elisa Belluzzi ◽

Elena Stocco ◽

Assunta Pozzuoli ◽

Marnie Granzotto ◽

Andrea Porzionato ◽

...

Keyword(s):

Synovial Membrane ◽

Adult Population ◽

Joint Damage ◽

Joint Disease ◽

Infrapatellar Fat Pad ◽

Fat Pad ◽

Pain Mechanisms ◽

Knee Oa ◽

New Findings

Osteoarthritis (OA) is the most common form of joint disease and a major cause of pain and disability in the adult population. Interestingly, there are patients with symptomatic OA displaying pain, while patients with asymptomatic OA that do not experience pain but show radiographic signs of joint damage. Pain is a complex experience integrating sensory, affective, and cognitive processes related to several peripheral and central nociceptive factors besides inflammation. During the last years, the role of infrapatellar fat pad (IFP), other than the synovial membrane, has been investigated as a potential source of pain in OA. Interestingly, new findings suggest that IFP and synovial membrane might act as a functional unit in OA pathogenesis and pain. The present review discuss the role of IFP and synovial membrane in the development of OA, with a particular focus on pain onset and the possible involved mediators that may play a role in OA pathology and pain mechanisms. Inflammation of IFP and synovial membrane may drive peripheral and central sensitization in KOA. Since sensitization is associated with pain severity in knee OA and may potentially contribute to the transition from acute to chronic, persistent pain in knee OA, preventing sensitization would be a potentially effective and novel means of preventing worsening of pain in knee OA.

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Quantitatively Measured Infrapatellar Fat Pad Signal Intensity Alteration is Associated with Joint Effusion-Synovitis in Knee Osteoarthritis

10.21203/rs.3.rs-404837/v1 ◽

2021 ◽

Author(s):

Guangfeng Ruan ◽

Yan Zhang ◽

Zhaohua Zhu ◽

Peihua Cao ◽

Xiaoshuai Wang ◽

...

Keyword(s):

Signal Intensity ◽

High Signal Intensity ◽

Joint Effusion ◽

Infrapatellar Fat Pad ◽

High Signal ◽

Fat Pad ◽

Knee Oa ◽

Suprapatellar Pouch ◽

Intensity Region

Abstract Background: Abnormal infrapatellar fat pad (IPFP) plays a detrimental role in knee osteoarthritis (OA) by producing pro-inflammatory cytokines. IPFP may interact with synovium because of their adjacent anatomical positions; however, whether abnormal IPFP can contribute to effusion-synovitis in knee OA is unclear.Methods: Among 255 knee OA patients, IPFP signal intensity alteration represented by four measurement parameters [standard deviation of IPFP signal intensity (IPFP sDev), upper quartile value of IPFP high signal intensity region (IPFP UQ (H)), ratio of IPFP high signal intensity region volume to whole IPFP volume (IPFP percentage (H)), and clustering factor of IPFP high signal intensity (IPFP clustering factor (H))] was measured quantitatively at baseline and two-year follow-up using magnetic resonance imaging (MRI). Effusion-synovitis of the suprapatellar pouch and other cavities were measured both quantitatively and semi-quantitatively as effusion-synovitis volume and effusion-synovitis score at baseline and two-year follow-up using MRI. Mixed-effects models were used to assess the associations between IPFP signal intensity alteration and effusion-synovitis over two years.Results: In multivariable analyses, all four parameters of IPFP signal intensity alteration were positively associated with total effusion-synovitis volume and effusion-synovitis volumes of the suprapatellar pouch and of other cavities over two years (all P＜0.05). They were also associated with the semi-quantitative measure of effusion-synovitis except for IPFP percentage (H) with effusion-synovitis in other cavities. Conclusion: Quantitatively measured IPFP signal intensity alteration is positively associated with joint effusion-synovitis in people with knee OA, suggesting that IPFP signal intensity alteration may contribute to effusion-synovitis and a coexistent pattern of these two imaging biomarkers could exist in knee OA patients.

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Inflammatory Cells in Patients with Endstage Knee Osteoarthritis: A Comparison between the Synovium and the Infrapatellar Fat Pad

The Journal of Rheumatology ◽

10.3899/jrheum.151068 ◽

2016 ◽

Vol 43 (4) ◽

pp. 771-778 ◽

Cited By ~ 51

Author(s):

Inge R. Klein-Wieringa ◽

Badelog J.E. de Lange-Brokaar ◽

Erlangga Yusuf ◽

Stefan N. Andersen ◽

Joanneke C. Kwekkeboom ◽

...

Keyword(s):

T Cells ◽

Proinflammatory Cytokines ◽

Immune Cells ◽

Cd4 T Cells ◽

Inflammatory Cells ◽

Infrapatellar Fat Pad ◽

Fat Pad ◽

Activation Markers ◽

Knee Oa ◽

Activated State

Objective.To get a better understanding of inflammatory pathways active in the osteoarthritic (OA) joint, we characterized and compared inflammatory cells in the synovium and the infrapatellar fat pad (IFP) of patients with knee OA.Methods.Infiltrating immune cells were characterized by flow cytometry in 76 patients with knee OA (mean age 63.3, 52% women, median body mass index 28.9) from whom synovial tissue (n = 40) and IFP (n = 68) samples were obtained. Pain was assessed by the visual analog scale (VAS; 0–100 mm). Spearman rank correlations and linear regression analyses adjusted for sex and age were performed.Results.Macrophages and T cells, followed by mast cells, were the most predominant immune cells in the synovium and IFP, and were equally abundant in these tissues. Macrophages and T cells secreted mostly proinflammatory cytokines even without additional stimulation, indicating their activated state. Accordingly, most CD4+ T cells had a memory phenotype and contained a significant population of cells expressing activation markers (CD25+, CD69+). Interestingly, the percent of CD69+ T cells was higher in synovial than IFP CD4+ T cells. Preliminary analyses indicated that the number of synovial CD4+ T cells were associated with VAS pain (β 0.51, 95% CI 0.09–1.02, p = 0.02).Conclusion.Our data suggest that the immune cell composition of the synovium and the IFP is similar, and includes activated cells that could contribute to inflammation through secretion of proinflammatory cytokines. Moreover, preliminary analyses indicate that synovial CD4+ T cells might associate with pain in patients with endstage OA of the knee.

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Induction of an Inflammatory and Prodegradative Phenotype in Autologous Fibroblast-like Synoviocytes by the Infrapatellar Fat Pad From Patients With Knee Osteoarthritis

Arthritis & Rheumatology ◽

10.1002/art.38657 ◽

2014 ◽

Vol 66 (8) ◽

pp. 2165-2174 ◽

Cited By ~ 64

Author(s):

Florent Eymard ◽

Audrey Pigenet ◽

Danièle Citadelle ◽

Charles-Henri Flouzat-Lachaniette ◽

Alexandre Poignard ◽

...

Keyword(s):

Knee Osteoarthritis ◽

Infrapatellar Fat Pad ◽

Fat Pad ◽

Fibroblast Like Synoviocytes

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The clinical efficacy of arthroscopic therapy with knee infrapatellar fat pad cell concentrates in treating knee cartilage lesion: a prospective, randomized, and controlled study

Journal of Orthopaedic Surgery and Research ◽

10.1186/s13018-021-02224-9 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Yiqin Zhou ◽

Haobo Li ◽

Dong Xiang ◽

Jiahua Shao ◽

Qiwei Fu ◽

...

Keyword(s):

Clinical Efficacy ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Knee Arthroscopy ◽

Infrapatellar Fat Pad ◽

Control Group ◽

Knee Cartilage ◽

Fat Pad ◽

Group 12 ◽

Significant Difference

Abstract Introduction To evaluate the clinical efficacy of arthroscopic therapy with infrapatellar fat pad cell concentrates in treating knee cartilage lesions, we conducted a prospective randomized single-blind clinical study of controlled method. Methods Sixty cases from Shanghai Changzheng Hospital from April 2018 to December 2019 were chosen and randomly divided into 2 groups equally. Patients in the experiment group were treated through knee arthroscopy with knee infrapatellar fat pad cell concentrates containing mesenchymal stromal cells, while patients in the control group were treated through regular knee arthroscopic therapy. VAS and WOMAC scores were assessed at pre-operation, and 6 weeks, 12 weeks, 6 months, and 12 months after intervention. MORCART scores were assessed at pre-operation and 12 months after intervention. Results Twenty-nine cases in the experiment group and 28 cases in the control group were followed up. No significant difference in VAS, WOMAC, and MOCART scores were found between the two groups before surgery (P > 0.05). The WOMAC total and WOMAC function scores of the experiment group were significantly lower than those of the control group 6 months and 12 months after surgery (P < 0.05). The VAS rest and VAS motion scores of the experiment group were found significantly lower than those of the control group 12 months after surgery (P < 0.05). The MOCART scores of the experiment group were found significantly higher compared with the control group 12 months after surgery (P < 0.05). No significant difference in WOMAC stiffness scores were found between the two groups. Conclusions The short-term results of our study are encouraging and demonstrate that knee arthroscopy with infrapatellar fat pad cell concentrates containing mesenchymal stromal cells is safe and provides assistance in reducing pain and improving function in patients with knee cartilage lesions. Trial registration ChiCTR1800015379. Registered on 27 March 2018, http://www.chictr.org.cn/showproj.aspx?proj=25901.

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