bluuebunny/crossref_metadata_2025 huggingface dataset:
Foot pain: Is current or past shoewear a factor?
Authors: Dufour Alyssa B. , Broe Kerry E. , Nguyen Uyen‐Sa D. T. , Gagnon David R. , Hillstrom Howard J. , Walker Anne H. , Kivell Erin , Hannan Marian T.
Published: September 2009

Objective

Foot pain is common, yet few studies have examined the condition in relationship to shoewear. In this cross‐sectional study of men and women from the population‐based Framingham Study, the association between foot pain and type of shoewear was examined.

Methods

Data were collected on 3,378 members of the Framingham Study who completed the foot examination in 2002–2008. Foot pain (both generalized and at specific locations) was measured by the response to the question “On most days, do you have pain, aching or stiffness in either foot?” Shoewear was recorded for the present time and 5 past age categories, by the subject's choice of the appropriate shoe from a list. The responses were categorized into 3 groups (good, average, or poor shoes). Sex‐specific multivariate logistic regression models were used to examine the effect of shoewear (average shoes were the referent group) on generalized and location‐specific foot pain, adjusting for age and weight.

Results

In women, compared with average shoes, those who wore good shoes in the past were 67% less likely to report hindfoot pain (P = 0.02), after adjusting for age and weight. In men, there was no association between foot pain, at any location, and shoewear, possibly due to the fact that <2% wore bad shoe types, making it difficult to see any relationship.

Conclusion

Even after taking age and weight into account, past shoewear use in women remained associated with hindfoot pain. Future studies should address specific support and structural features of shoewear.
Clinical and genetic factors predictive of mortality in early systemic sclerosis
Authors: Assassi Shervin , del Junco Deborah , Sutter Kari , McNearney Terry A. , Reveille John D. , Karnavas Andrew , Gourh Pravitt , Estrada‐Y‐Martin Rosa M. , Fischbach Michael , Arnett Frank C. , Mayes Maureen D.
Published: September 2009

Objective

To investigate the clinical and genetic variables at initial presentation that predict survival in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) cohort.

Methods

GENISOS is a prospective, observational study of a multiethnic early systemic sclerosis (SSc) cohort. To date, a total of 250 patients have been enrolled. In addition to clinical and laboratory data, electrocardiograms (EKGs), chest radiographs, and pulmonary function tests have been obtained from each patient. A modified Rodnan skin thickness score, HLA class II genotyping, and a Medsger Damage Index also have been collected. We performed multivariable analyses utilizing the Cox regression following a purposeful model building strategy.

Results

The study analyzed 122 white, 47 African American, and 71 Hispanic SSc patients with an average disease duration of 2.6 years at enrollment. At the time of analysis, 52 (20.8%) of the 250 patients had died. In the final multivariable model excluding HLA genes, 7 variables emerged as significant predictors of mortality: age ≥65 years at enrollment, forced vital capacity <50% predicted, clinically significant arrhythmia on EKG, absence of anticentromere antibodies, hypertension, chest radiograph suggestive of pulmonary fibrosis, and low body mass index (BMI). In separate modeling that included HLA genes, HLA alleles DRB1*0802 and DQA1*0501 were significant predictors of mortality in addition to the predictors mentioned above.

Conclusion

A limited number of variables collected at presentation, including BMI, are able to predict mortality in patients with early SSc. In addition, some of the HLA genes associated with SSc susceptibility are useful for predicting SSc outcome.
Knee osteoarthritis in obese women with cardiometabolic clustering
Authors: Sowers Maryfran , Karvonen‐Gutierrez Carrie A. , Palmieri‐Smith Riann , Jacobson Jon A. , Jiang Yebin , Ashton‐Miller James A.
Published: September 2009

Objective

To assess the role of obesity and metabolic dysfunctionality with knee osteoarthritis (OA), knee joint pain, and physical functioning performance, adjusted for joint space width (JSW) asymmetry.

Methods

Knee OA was defined as a Kellgren/Lawrence score ≥2 on weight‐bearing radiographs. Obesity was defined as a body mass index ≥30 kg/m2. Cardiometabolic clustering classification was based on having ≥2 of the following factors: low levels of high‐density lipoprotein cholesterol; elevated levels of low‐density lipoprotein cholesterol, triglycerides, blood pressure, C‐reactive protein, waist:hip ratio, or glucose; or diabetes mellitus. The difference between lateral and medial knee JSW was used to determine joint space asymmetry.

Results

In a sample of women (n = 482, mean age 47 years), prevalences of knee OA and persistent knee pain were 11% and 30%, respectively. The knee OA prevalence in nonobese women without cardiometabolic clustering was 4.7%, compared with 12.8% in obese women without cardiometabolic clustering and 23.2% in obese women with cardiometabolic clustering. Nonobese women without cardiometabolic clustering were less likely to perceive themselves as limited compared with women in all other obesity/cardiometabolic groups (P < 0.05). Similar associations were seen with knee pain and physical functioning measures. The inclusion of a joint space asymmetry measure was associated with knee OA but not with knee pain or physical functioning.

Conclusion

Knee OA was twice as frequent in obese women with cardiometabolic clustering compared with those without, even when considering age and joint asymmetry. Obesity/cardiometabolic clustering was also associated with persistent knee pain and impaired physical functioning.
Risk factors for upper‐extremity musculoskeletal disorders in the working population
Authors: Roquelaure Yves , Ha Catherine , Rouillon Clarisse , Fouquet Natacha , Leclerc Annette , Descatha Alexis , Touranchet Annie , Goldberg Marcel , Imbernon Ellen ,   Members of Occupational Health Services of the Pays de la Loire Region
Published: September 2009

Objective

To assess the relative importance of personal and occupational risk factors for upper‐extremity musculoskeletal disorders in the working population.

Methods

A total of 3,710 workers (58% men) participating in a surveillance program of musculoskeletal disorders in a French region in 2002–2005 were included. Upper‐extremity musculoskeletal disorders were diagnosed by 83 trained occupational physicians performing a standardized physical examination. Personal factors and work exposure were assessed by a self‐administered questionnaire. Statistical associations between musculoskeletal disorders, personal, and occupational factors were analyzed using logistic regression modeling.

Results

A total of 472 workers experienced at least 1 upper‐extremity musculoskeletal disorder. The risk of upper‐extremity musculoskeletal disorders increased with age for both sexes (P < 0.001, odds ratio [OR] ≤4.9 in men and ≤5.0 in women), and in cases of prior history of upper‐extremity musculoskeletal disorders (OR 3.1 and 5.0, respectively, P < 0.001). In men, upper‐extremity musculoskeletal disorders were associated with obesity (OR 2.2, P = 0.014), high level of physical demand (OR 2.0, P < 0.001), high repetitiveness of the task (OR 1.5, P = 0.027), postures with the arms at or above shoulder level (OR 1.7, P = 0.009) or with full elbow flexion (OR 1.6, P = 0.006), and high psychological demand (OR 1.5, P = 0.005). In women, upper‐extremity musculoskeletal disorders were associated with diabetes mellitus (OR 4.9, P = 0.001), postures with extreme wrist bending (OR 2.0, P < 0.001), use of vibrating hand tools (OR 2.2, P = 0.025), and low level of decision authority (OR 1.4, P = 0.042).

Conclusion

Personal and work‐related physical and psychosocial factors were strongly associated with clinically diagnosed upper‐extremity musculoskeletal disorders.
Recurrence rates of cardiac manifestations associated with neonatal lupus and maternal/fetal risk factors
Authors: Llanos Carolina , Izmirly Peter M. , Katholi Margaret , Clancy Robert M. , Friedman Deborah M. , Kim Mimi Y. , Buyon Jill P.
Published: September 2009

Objective

Identifying the frequency of recurrent cardiac manifestations of neonatal lupus (NL) in a second child is critical to understanding the pathogenesis of anti‐SSA/Ro–mediated injury and would improve counseling strategies regarding future pregnancies and power the design of clinical prevention trials. Accordingly, this study was undertaken to address the recurrence rates of cardiac NL and associated risk factors in a large US‐based cohort.

Methods

Families enrolled in the Research Registry for Neonatal Lupus were evaluated for rates of recurrence of cardiac NL and potential risk factors, with a focus on pregnancies immediately following the birth of an affected child.

Results

The overall rate of recurrence of cardiac NL in 161 pregnancies of 129 mothers with anti‐SSA/Ro antibodies was 17.4% (95% confidence interval 11.1–23.6%). Analysis of the potential risk factors among 129 mothers with a pregnancy immediately following the birth of a child with cardiac NL showed that the maternal diagnosis was not associated with the outcome in a subsequent pregnancy. In this group, 23% of mothers who were either asymptomatic or had an undifferentiated autoimmune syndrome, compared with 14% of mothers with systemic lupus erythematosus or Sjögren's syndrome, had a second child with cardiac NL (P = 0.25). The recurrence rate was not statistically significantly different in mothers who had taken steroids compared with those who had not taken steroids (16% versus 21%; P = 0.78). The antibody status of the mother was not predictive of outcome in subsequent pregnancies. Moreover, death of the first child with cardiac NL was not predictive of recurrence of cardiac NL in a subsequent pregnancy (P = 0.31). The risk of cardiac NL was similar between male and female children (17.2% versus 18.3%; P = 1.0).

Conclusion

In this cohort, the overall recurrence rate for cardiac NL was 17%. The recurrence rate appeared to be unaffected by maternal health, use of steroids, antibody status, severity of cardiac disease in the first affected child, or sex of the subsequent child.
Antineutrophil cytoplasmic antibody–associated vasculitides: Could geographic patterns be explained by ambient ultraviolet radiation?
Authors: Gatenby Paul A. , Lucas Robyn M. , Engelsen Ola , Ponsonby Anne‐Louise , Clements Mark
Published: September 2009

Objective

This ecological study describes and quantifies the association between ambient ultraviolet (UV) radiation levels, including daily winter vitamin D effective UV radiation levels and the incidence of the 3 antineutrophil cytoplasmic antibody–associated vasculitides (AAVs): Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), and Churg‐Strauss syndrome (CSS). Latitudinal variation in occurrence of the AAVs, especially WG, has been previously reported. For other autoimmune diseases such as multiple sclerosis and type 1 diabetes mellitus, inverse associations with latitude are hypothesized to indicate a causative role for low UV radiation exposure, possibly acting via vitamin D status.

Methods

Published epidemiologic studies provided data on incident cases, total population of study regions, age‐specific incidence rates, and study location. From these data and online age‐specific population data, we calculated crude incidence rates, the expected number of cases (to control for possible age confounding), and measures of ambient UV radiation. Negative binomial regression models were used to calculate the incidence rate ratio (IRR) for a 1,000 joules/m2 increase in ambient UV radiation.

Results

The incidence of WG and CSS increased with increasing latitude and decreasing ambient UV radiation, with a stronger and more consistent effect across different UV radiation measures for WG, e.g., for average daily ambient clear sky erythemal UV radiation (WG: IRR 0.64 [95% confidence interval (95% CI) 0.44–0.94], P = 0.02; CSS: IRR 0.67 [95% CI 0.43–1.05], P = 0.08; MPA: IRR 1.16 [95% CI 0.92–1.47], P = 0.22). There was no apparent latitudinal variation in MPA incidence.

Conclusion

Our findings are consistent with a protective immunomodulatory effect of ambient UV radiation on the onset of WG and CSS. We discuss possible mechanisms, including the effect of vitamin D on the immune system.
Abnormal function of high‐density lipoprotein is associated with poor disease control and an altered protein cargo in rheumatoid arthritis
Authors: Charles‐Schoeman Christina , Watanabe Junji , Lee Yuen Yin , Furst Daniel E. , Amjadi Sogol , Elashoff David , Park Grace , McMahon Maureen , Paulus Harold E. , Fogelman Alan M. , Reddy Srinivasa T.
Published: September 2009

Objective

To characterize the antiinflammatory function of high‐density lipoprotein (HDL) in patients with rheumatoid arthritis (RA) and to identify specific differences in HDL‐associated proteins and enzymes that distinguish proinflammatory HDL from normal, antiinflammatory HDL.

Methods

We studied 132 RA patients. The antiinflammatory function of HDL was assessed by a cell‐free assay, and proinflammatory HDL was defined by an HDL inflammatory index ≥1. Plasma and HDL‐associated protein levels of apolipoprotein A‐I (Apo A‐I), haptoglobin, hemopexin, hemoglobin, and myeloperoxidase (MPO) were measured by direct and sandwich enzyme‐linked immunosorbent assays, respectively. Lecithin:cholesterol acyltransferase (LCAT) activity was measured by a commercially available assay.

Results

Age, disease activity, the presence of erosive disease, non‐Caucasian race, and smoking were significantly associated with proinflammatory HDL on multivariate analysis. Patients with proinflammatory HDL had higher measures of systemic inflammation, and a significant correlation was observed between RA disease activity (using the Disease Activity Score in 28 joints) and the HDL inflammatory index (r = 0.54, P < 0.0001). Compared with patients with antiinflammatory HDL, patients with proinflammatory HDL had significantly higher levels of haptoglobin, hemoglobin, Apo A‐I, and MPO associated with HDL (P < 0.05 for all comparisons except MPO, which was P = 0.05). LCAT activity was lowest in patients with proinflammatory HDL, but was also significantly reduced in RA patients with antiinflammatory HDL as compared with healthy controls (P = 0.001).

Conclusion

Proinflammatory HDL in this RA patient cohort was associated with active disease and an altered protein cargo as compared with antiinflammatory HDL in RA patients and in healthy controls. The antiinflammatory function of HDL was inversely correlated with systemic inflammation in RA patients and may warrant further investigation as a mechanism by which active RA increases cardiovascular morbidity and mortality.
Induction of bovine articular chondrocyte senescence with oxidized low‐density lipoprotein through lectin‐like oxidized low‐density lipoprotein receptor 1
Authors: Zushi Satoshi , Akagi Masao , Kishimoto Hideki , Teramura Takeshi , Sawamura Tatsuya , Hamanishi Chiaki
Published: September 2009

Objective

Findings of recent in vivo and in vitro studies suggest that oxidized low‐density lipoprotein (ox‐LDL) plays a role in the degeneration of cartilage. The purpose of this study was to determine whether ox‐LDL induces chondrocyte senescence through binding to lectin‐like ox‐LDL receptor 1 (LOX‐1).

Methods

The effects of ox‐LDL on senescence of cultured bovine articular chondrocytes (BACs) were investigated by observing senescence‐associated (SA) β‐galactosidase (β‐gal) activity, cell proliferation activity, and telomerase activity. Telomerase activity was measured after adding LY294002 (a specific inhibitor of phosphatidylinositol 3‐kinase [PI3K]) or after adding insulin‐like growth factor 1 (IGF‐1; an activator of PI3K) plus ox‐LDL to the culture medium to elucidate the involvement of the PI3K/Akt pathway. Immunoblot analysis was used to investigate whether ox‐LDL affects the phosphorylation of Akt. To ascertain whether these effects were attributable to ox‐LDL binding to LOX‐1, BACs were preincubated with TS‐20, an anti‐bovine LOX‐1 blocking antibody.

Results

The activity of SA β‐gal was increased and the incorporation of bromodeoxyuridine into BACs was decreased by ox‐LDL in a dose‐dependent manner. The telomerase activity of BACs was suppressed by the addition of ox‐LDL in a time‐ and dose‐dependent manner. LY294002 suppressed the telomerase activity of BACs, and IGF‐1 reversed the ox‐LDL–induced suppression of telomerase activity. In addition, ox‐LDL rapidly decreased the amount of phosphorylated Akt in BACs. Pretreatment of cultured BACs with TS‐20 recovered these effects.

Conclusion

These data show that ox‐LDL binding to LOX‐1 induces stress‐induced premature senescence of chondrocytes and results in suppression of telomerase activity by inactivating the PI3K/Akt pathway. Oxidized LDL may play an important role in the pathogenesis of osteoarthritis by inducing chondrocyte senescence.
Induction of an antiinflammatory effect and prevention of cartilage damage in rat knee osteoarthritis by CF101 treatment
Authors: Bar‐Yehuda S. , Rath‐Wolfson L. , Del Valle L. , Ochaion A. , Cohen S. , Patoka R. , Zozulya G. , Barer F. , Atar E. , Piña‐Oviedo S. , Perez‐Liz G. , Castel D. , Fishman P.
Published: September 2009

Objective

Studies have suggested that rheumatoid arthritis (RA) and osteoarthritis (OA) share common characteristics. The highly selective A3 adenosine receptor agonist CF101 was recently defined as a potent antiinflammatory agent for the treatment of RA. The purpose of this study was to examine the effects of CF101 on the clinical and pathologic manifestations of OA in an experimental animal model.

Methods

OA was induced in rats by monosodium iodoacetate, and upon disease onset, oral treatment with CF101 (100 μg/kg given twice daily) was initiated. The A3 adenosine receptor antagonist MRS1220 (100 μg/kg given twice daily) was administered orally, 30 minutes before CF101 treatment. The OA clinical score was monitored by knee diameter measurements and by radiographic analyses. Histologic analyses were performed following staining with hematoxylin and eosin, Safranin O–fast green, or toluidine blue, and histologic changes were scored according to a modified Mankin system. Signaling proteins were assayed by Western blotting; apoptosis was detected via immunohistochemistry and TUNEL analyses.

Results

CF101 induced a marked decrease in knee diameter and improved the changes noted on radiographs. Administration of MRS1220 counteracted the effects of CF101. CF101 prevented cartilage damage, osteoclast/osteophyte formation, and bone destruction. In addition, CF101 markedly reduced pannus formation and lymphocyte infiltration. Mechanistically, CF101 induced deregulation of the NF‐κB signaling pathway, resulting in down‐regulation of tumor necrosis factor α. Consequently, CF101 induced apoptosis of inflammatory cells that had infiltrated the knee joints; however, it prevented apoptosis of chondrocytes.

Conclusion

CF101 deregulated the NF‐κB signaling pathway involved in the pathogenesis of OA. CF101 induced apoptosis of inflammatory cells and acted as a cartilage protective agent, which suggests that it would be a suitable candidate drug for the treatment of OA.
Plasmin immunization preferentially induces potentially prothrombotic IgG anticardiolipin antibodies in MRL/MpJ mice
Authors: Ede Kaleo , Hwang Kwan‐Ki , Wu Chen‐Ching , Wu Meifang , Yang Yao‐Hsu , Lin Wei‐Shiang , Chien Daniel , Chen Pei‐Chih , Tsao Betty P. , McCurdy Deborah K. , Chen Pojen P.
Published: September 2009

Objective

To test the hypothesis, utilizing 2 experimental mouse models, that plasmin is an important autoantigen that drives the production of certain IgG anticardiolipin (aCL) antibodies in patients with the antiphospholipid syndrome.

Methods

BALB/cJ and MRL/MpJ mice were immunized with Freund's complete adjuvant in the presence or absence of human plasmin. The mouse sera were analyzed for production of IgG antiplasmin, IgG aCL, and IgG anti–β2‐glycoprotein I (anti‐β2GPI) antibodies. IgG monoclonal antibodies (mAb) were generated from the plasmin‐immunized MRL/MpJ mice with high titers of aCL, and these 10 mAb were studied for their binding properties and functional activity in vitro.

Results

Plasmin‐immunized BALB/cJ mice produced high titers of IgG antiplasmin only, while plasmin‐immunized MRL/MpJ mice produced high titers of IgG antiplasmin, IgG aCL, and IgG anti‐β2GPI. Both strains of mice immunized with the adjuvant alone did not develop IgG antiplasmin or IgG aCL. All 10 of the IgG mAb bound to human plasmin and cardiolipin, while 4 of 10 bound to β2GPI, 3 of 10 bound to thrombin, and 4 of 10 bound to the activated coagulation factor X (FXa). Functionally, 4 of the 10 IgG mAb inhibited plasmin activity, 1 of 10 hindered inactivation of thrombin by antithrombin III, and 2 of 10 inhibited inactivation of FXa by antithrombin III.

Conclusion

Plasmin immunization leads to production of IgG antiplasmin, aCL, and anti‐β2GPI in MRL/MpJ mice, but leads to production of only IgG antiplasmin in BALB/cJ mice. IgG mAb generated from plasmin‐immunized MRL/MpJ mice bind to various antigens and exhibit procoagulant activity in vitro. These results suggest that plasmin may drive potentially prothrombotic aCL in genetically susceptible individuals.
Skeletal health among African Americans with recent‐onset rheumatoid arthritis
Authors: Curtis J. R. , Arora T. , Donaldson M. , Alarcón G. S. , Callahan L. F. , Moreland L. W. , Bridges S. L. , Mikuls T. R.
Published: September 2009

Objective

African Americans with rheumatoid arthritis (RA) may be at increased fracture risk. We applied the World Health Organization (WHO) Fracture Risk Assessment Tool (FRAX) and National Osteoporosis Foundation (NOF) guidelines to a cohort of African Americans with early RA to identify which patients were recommended for osteoporosis treatment.

Methods

Risk factors and bone mineral density (BMD) were assessed in a cohort of African Americans with RA. The WHO FRAX tool estimated 10‐year fracture risk. Patients were risk stratified using FRAX without BMD to identify which individuals might be most efficiently targeted for BMD testing.

Results

Participants (n = 324) had a mean age of 51 years and included 81% women. There were no associations of RA disease characteristics with BMD. The proportion of patients recommended for osteoporosis treatment varied from 3–86%, depending on age and body mass index (BMI). Ten‐year fracture risk calculated with BMI only was generally the same or higher than fracture risk calculated with BMD; adding BMD data provided the most incremental value to risk assessment in patients 55–69 years of age with low/normal BMI, and in those ≥70 years of age with BMI ≥30 kg/m2.

Conclusion

A high proportion of African Americans with RA were recommended for treatment under the 2008 NOF guidelines. FRAX without BMD identified low‐risk patients accurately. Systematic application of FRAX to screen high‐risk groups such as patients with RA may be used to target individuals for BMD testing and reduce the use of unnecessary tests and treatments.
CCR5 is involved in resolution of inflammation in proteoglycan‐induced arthritis
Authors: Doodes Paul D. , Cao Yanxia , Hamel Keith M. , Wang Yumei , Rodeghero Rachel L. , Kobezda Tamas , Finnegan Alison
Published: September 2009

Objective

CCR5 and its ligands (CCL3, CCL4, and CCL5) may play a role in inflammatory cell recruitment into the joint. However, it was recently reported that CCR5 on T cells and neutrophils acts as a decoy receptor for CCL3 and CCL5 to assist in the resolution of inflammation. The aim of this study was to determine whether CCR5 functions as a proinflammatory or antiinflammatory mediator in arthritis, by examining the role of CCR5 in proteoglycan (PG)–induced arthritis (PGIA).

Methods

Arthritis was induced by immunizing wild‐type (WT) and CCR5‐deficient (CCR5−/−) BALB/c mice with human PG in adjuvant. The onset and severity of PGIA were monitored over time. Met‐RANTES was used to block CCR5 in vivo. Arthritis was transferred to SCID mice, using spleen cells from arthritic WT and CCR5−/− mice. The expression of cytokines and chemokines was measured by enzyme‐linked immunosorbent assay.

Results

In CCR5−/− mice and WT mice treated with the CCR5 inhibitor Met‐RANTES, exacerbated arthritis developed late in the disease course. The increase in arthritis severity in CCR5−/− mice correlated with elevated serum levels of CCL5. However, exacerbated arthritis was not intrinsic to the CCR5−/− lymphoid cells, because the arthritis that developed in SCID mouse recipients was similar to that in WT and CCR5−/− mice. CCR5 expression in the SCID mouse was sufficient to clear CCL5, because serum levels of CCL5 were the same in SCID mouse recipients receiving cells from either WT or CCR5−/− mice.

Conclusion

These data demonstrate that CCR5 is a key player in controlling the resolution of inflammation in experimental arthritis.
Parathyroid hormone 1–34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats
Authors: Chang Je‐Ken , Chang Ling‐Hwa , Hung Shao‐Hung , Wu Shun‐Cheng , Lee Hsin‐Yi , Lin Yi‐Shan , Chen Chung‐Hwan , Fu Yin‐Chih , Wang Gwo‐Jaw , Ho Mei‐Ling
Published: September 2009

Objective

Parathyroid hormone 1–34 (PTH[1–34]), a parathyroid hormone analog, shares the same receptor, PTH receptor 1, with parathyroid hormone–related peptide (PTHrP). This study was undertaken to address the hypothesis that PTH(1–34) inhibits terminal differentiation of articular chondrocytes and in turn suppresses the progression of osteoarthritis (OA).

Methods

We studied the effect of PTH(1–34) on human articular chondrocytes with azacytidine (azaC)–induced terminal differentiation in vitro and on papain‐induced OA in the knee joints of rats. In the in vitro study, we measured the levels of messenger RNA for SOX9, aggrecan, type II collagen, type X collagen, alkaline phosphatase (AP), Indian hedgehog (IHH), Bcl‐2, and Bax by real‐time polymerase chain reaction, levels of glycosaminoglycan (GAG) by dimethylmethylene blue assay, and rate of apoptosis by TUNEL staining. In the in vivo study, we evaluated the histologic changes in GAG, type II collagen, type X collagen, and chondrocyte apoptosis in the articular cartilage of rat knees.

Results

AzaC induced terminal differentiation of human chondrocytes, including down‐regulation of aggrecan, type II collagen, and GAG and up‐regulation of type X collagen, alkaline phosphatase, and IHH. Apoptosis was reversed by 3–10 days of treatment with 10 nM PTH(1–34). SOX9 expression was not changed by either azaC or PTH(1–34) treatment. Bcl‐2 and Bax were up‐regulated on day 10 and day 14, respectively, after azaC induction of terminal differentiation, but PTH(1–34) treatment did not reverse this effect. Furthermore, PTH(1–34) treatment reversed papain‐induced OA changes (decreasing GAG and type II collagen, and increasing type X collagen and chondrocyte apoptosis) in the knee joints of rats.

Conclusion

Our findings indicate that PTH(1–34) inhibits the terminal differentiation of human articular chondrocytes in vitro and inhibits progression of OA in rats in vivo, and may be used to treat OA.
Human inflammatory synovial fibroblasts induce enhanced myeloid cell recruitment and angiogenesis through a hypoxia‐inducible transcription factor 1α/vascular endothelial growth factor–mediated pathway in immunodeficient mice
Authors: del Rey Manuel J. , Izquierdo Elena , Caja Sergio , Usategui Alicia , Santiago Begoña , Galindo María , Pablos José L.
Published: September 2009

Objective

Hyperplasia and phenotypic changes in fibroblasts are often observed in chronic inflammatory lesions, and yet the autonomous pathogenic contribution of these changes is uncertain. The purpose of this study was to analyze the intrinsic ability of fibroblasts from chronically inflamed synovial tissue to drive cell recruitment and angiogenesis.

Methods

Fibroblasts from patients with rheumatoid arthritis (RA) or osteoarthritis (OA), as well as fibroblasts from healthy synovial tissue and healthy skin, were cultured and subcutaneously engrafted into immunodeficient mice. Cell infiltration and angiogenesis were analyzed in the grafts by immunohistochemical studies. The role of vascular endothelial growth factor (VEGF), CXCL12, and hypoxia‐inducible transcription factor 1α (HIF‐1α) in these processes was investigated using specific antagonists or small interfering RNA (siRNA)–mediated down‐regulation of HIF‐1α in fibroblasts.

Results

Inflammatory (OA and RA) synovial fibroblasts, compared with healthy dermal or synovial tissue fibroblasts, induced a significant enhancement in myeloid cell infiltration and angiogenesis in immunodeficient mice. These activities were associated with increased constitutive and hypoxia‐induced expression of VEGF, but not CXCL12, in inflammatory fibroblasts compared with healthy fibroblasts. VEGF and CXCL12 antagonists significantly reduced myeloid cell infiltration and angiogenesis. Furthermore, targeting of HIF‐1α expression by siRNA or of HIF‐1α transcriptional activity by the small molecule chetomin in RA fibroblasts significantly reduced both responses.

Conclusion

These results demonstrate that chronic synovial inflammation is associated with stable fibroblast changes that, under hypoxic conditions, are sufficient to induce inflammatory cell recruitment and angiogenesis, both of which are processes relevant to the perpetuation of chronic inflammation.
Prognostic factors in nonoperative therapy for chronic symptomatic calcific tendinitis of the shoulder
Authors: Ogon P. , Suedkamp N. P. , Jaeger M. , Izadpanah K. , Koestler W. , Maier D.
Published: September 2009

Objective

To define prognostic factors in chronically symptomatic patients with calcific tendinitis of the shoulder.

Methods

We evaluated 420 patients (488 shoulders) in the context of a prospective cohort study. Epidemiologic data were assessed. The radiographic and sonographic appearance of the calcific deposits was classified. The mean period of nonoperative therapy was 4.4 years (range 0.5–13.7 years). After referral to our institution, standardized nonoperative therapy was continued for a minimum of 3 months. Failure of nonoperative therapy was defined as the persistence of symptomatic calcific tendinitis of the shoulder after a minimum of 6 months. Prognostic factors (determined at P < 0.05 by chi‐square test) were analyzed by logistic regression.

Results

Of the 420 patients, 269 (64%) were women, 151 (36%) were men. The mean age of the patients was 51.3 years (range 28–84 years). Occurrence of calcific tendinitis of the shoulder was unilateral in 84% and bilateral in 16%. Gärtner type I calcific deposits were found in 37%, type II in 32%, and type III in 31%. Failure of nonoperative therapy was observed in 114 patients (27%). Negative prognostic factors were bilateral occurrence of calcific tendinitis of the shoulder, localization to the anterior portion of the acromion, medial (subacromial) extension, and high volume of the calcific deposit. Positive prognostic factors were a Gärtner type III deposit and a lack of sonographic sound extinction of the calcific deposit.

Conclusion

Our findings demonstrate the existence of prognostic factors in the nonoperative treatment of chronic symptomatic calcific tendinitis of the shoulder. Guidelines for optimal treatment can be implemented according to these factors to avoid a long‐term symptomatic disease course.
18F‐fluorodeoxyglucose–positron emission tomography scanning is more useful in followup than in the initial assessment of patients with Erdheim‐Chester disease
Authors: Arnaud Laurent , Malek Zoulikha , Archambaud Frédérique , Kas Aurélie , Toledano Dan , Drier Aurélie , Zeitoun Delphine , Cluzel Philippe , Grenier Philippe A. , Chiras Jacques , Piette Jean‐Charles , Amoura Zahir , Haroche Julien
Published: September 2009

Objective

Erdheim‐Chester disease (ECD) is a rare form of non–Langerhans' cell histiocytosis. The aim of this study was to assess the value of whole‐body scanning with 18F‐fluorodeoxyglucose–positron emission tomography (FDG‐PET) in a large cohort of ECD patients from a single center.

Methods

We retrospectively reviewed all PET scans performed on 31 patients with ECD who were referred to our department between 2005 and 2008. PET images were reviewed by 2 independent nuclear medicine specialist physicians and were compared with other imaging modalities performed within 15 days of each PET scan.

Results

Thirty‐one patients (10 women and 21 men; median age 59.5 years) underwent a total of 65 PET scans. Twenty‐three patients (74%) were untreated at the time of the initial PET scan, whereas 30 of the 34 followup PET scans (88%) were performed in patients who were undergoing immunomodulatory therapy. Comparison of the initial and followup PET scans with other imaging modalities revealed that the sensitivity of PET scanning varied greatly among the different organs studied (range 4.3–100%), while the specificity remained high (range 69.2–100%). Followup PET scans were particularly helpful in assessing central nervous system (CNS) involvement, since the PET scan was able to detect an early therapeutic response of CNS lesions, even before magnetic resonance imaging showed a decrease in their size. PET scanning was also very helpful in evaluating the cardiovascular system, which is a major prognostic factor in ECD, by assessing the heart and the entire vascular tree during a single session.

Conclusion

The results of our large, single‐center, retrospective study suggest that the findings of a FDG‐PET scan may be interesting in the initial assessment of patients with ECD, but its greater contribution is in followup of these patients.
Hypoxia‐inducible factor 1α inhibits the fibroblast‐like markers type I and type III collagen during hypoxia‐induced chondrocyte redifferentiation: Hypoxia not only induces type II collagen and aggrecan, but it also inhibits type I and type III collagen in the hypoxia‐inducible factor 1α–dependent redifferentiation of chondrocytes
Authors: Duval Elise , Leclercq Sylvain , Elissalde Jean‐Marc , Demoor Magali , Galéra Philippe , Boumédiene Karim
Published: September 2009

Objective

Autologous chondrocyte implantation requires expansion of cells ex vivo, leading to dedifferentiation of chondrocytes (loss of aggrecan and type II collagen to the profit of type I and type III collagens). Several approaches have been described for redifferentiation of these cells. Among them, low oxygen tension has been exploited to restore the differentiated chondrocyte phenotype, but molecular mechanisms of this process remain unclear. However, under conditions of hypoxia, one of the major factors involved is hypoxia‐inducible factor 1α (HIF‐1α). The purpose of this study was to investigate the role of HIF‐1α during human chondrocyte redifferentiation.

Methods

We used complementary approaches to achieving HIF‐1α loss (inhibition by cadmium ions and dominant‐negative expression) or gain (ectopic expression and cobalt ion treatment) of function. Expression of chondrocyte, as well as fibroblast‐like, phenotype markers was determined using real‐time reverse transcription–polymerase chain reaction and Western blot analyses. Binding activities of HIF‐1α and SOX9, a pivotal transcription factor of chondrogenesis, were evaluated by electrophoretic mobility shift assays and by chromatin immunoprecipitation assay.

Results

We found that hypoxia and HIF‐1α not only induced the expression of SOX9, COL2A1, and aggrecan, but they simultaneously inhibited the expression of COL1A1, COL1A2, and COL3A1. In addition, we identified the binding of HIF‐1α to the aggrecan promoter, the first such reported demonstration of this binding.

Conclusion

This study is the first to show a bimodal role of HIF‐1α in cartilage homeostasis, since HIF‐1α was shown to favor specific markers and to impair dedifferentiation. This suggests that manipulation of HIF‐1α could represent a promising approach to the treatment of osteoarthritis.
C1q inhibits immune complex–induced interferon‐α production in plasmacytoid dendritic cells: A novel link between C1q deficiency and systemic lupus erythematosus pathogenesis
Authors: Lood Christian , Gullstrand Birgitta , Truedsson Lennart , Olin Anders I. , Alm Gunnar V. , Rönnblom Lars , Sturfelt Gunnar , Eloranta Maija‐Leena , Bengtsson Anders A.
Published: September 2009

Objective

C1q deficiency is the strongest risk factor known for the development of systemic lupus erythematosus (SLE), since almost all humans with a genetic deficiency of C1q develop this disease. Low C1q serum concentration is also a typical finding in SLE during flares, emphasizing the involvement of C1q in SLE pathogenesis. Recent studies have revealed that C1q has a regulatory effect on Toll‐like receptor–induced cytokine production. Therefore, we undertook this study to investigate whether C1q could regulate production of interferon‐α (IFNα).

Methods

Peripheral blood mononuclear cells (PBMCs) and plasmacytoid dendritic cells (PDCs) were stimulated with 3 known interferogenic stimuli and cultured with physiologic concentrations of C1q. IFNα production was determined by an immunoassay.

Results

C1q significantly inhibited PBMC IFNα production induced by RNA‐containing immune complexes (ICs), herpes simplex virus (HSV), and CpG DNA. C1q also inhibited PDC IFNα production induced by ICs and CpG DNA but increased PDC IFNα production induced by HSV. The regulatory role of C1q was not specific for IFNα but was also seen for interleukin‐6 (IL‐6), IL‐8, and tumor necrosis factor α. We demonstrated binding of C1q to PDCs both by surface plasmon resonance interaction analysis and by flow cytometry, and we also demonstrated intracellular detection of 2 C1q binding proteins.

Conclusion

Our findings contribute to the understanding of why C1q deficiency is such a strong risk factor for SLE and suggest an explanation for the up‐regulation of the type I IFN system seen in SLE patients.
Extreme obesity due to impaired leptin signaling in mice does not cause knee osteoarthritis
Authors: Griffin Timothy M. , Huebner Janet L. , Kraus Virginia B. , Guilak Farshid
Published: September 2009

Objective

To test the hypothesis that obesity resulting from deletion of the leptin gene or the leptin receptor gene results in increased knee osteoarthritis (OA), systemic inflammation, and altered subchondral bone morphology.

Methods

Leptin‐deficient (ob/ob) and leptin receptor–deficient (db/db) female mice compared with wild‐type mice were studied, to document knee OA via histopathology. The levels of serum proinflammatory and antiinflammatory cytokines were measured using a multiplex bead immunoassay. Cortical and trabecular subchondral bone changes were documented by microfocal computed tomography, and body composition was quantified by dual x‐ray absorptiometry.

Results

Adiposity was increased by ∼10‐fold in ob/ob and db/db mice compared with controls, but it was not associated with an increased incidence of knee OA. Serum cytokine levels were unchanged in ob/ob and db/db mice relative to controls, except for the level of cytokine‐induced neutrophil chemoattractant (keratinocyte chemoattractant; murine analog of interleukin‐8), which was elevated. Leptin impairment was associated with reduced subchondral bone thickness and increased relative trabecular bone volume in the tibial epiphysis.

Conclusion

Extreme obesity due to impaired leptin signaling induced alterations in subchondral bone morphology without increasing the incidence of knee OA. Systemic inflammatory cytokine levels remained largely unchanged in ob/ob and db/db mice. These findings suggest that body fat, in and of itself, may not be a risk factor for joint degeneration, because adiposity in the absence of leptin signaling is insufficient to induce systemic inflammation and knee OA in female C57BL/6J mice. These results imply a pleiotropic role of leptin in the development of OA by regulating both the skeletal and immune systems.
No increased occurrence of ischemic heart disease prior to the onset of rheumatoid arthritis: Results from two Swedish population‐based rheumatoid arthritis cohorts
Authors: Holmqvist Marie E. , Wedrén Sara , Jacobsson Lennart T. H. , Klareskog Lars , Nyberg Fredrik , Rantapää‐Dahlqvist Solbritt , Alfredsson Lars , Askling Johan
Published: September 2009

Objective

To investigate the relative importance of shared etiologies for rheumatoid arthritis (RA) and ischemic heart disease (IHD) in terms of the well‐known increased risk of IHD in patients with RA, by assessing the occurrence of IHD up until the time of the onset of the first symptoms of RA.

Methods

We assessed the prevalence of a history of IHD, myocardial infarction (MI), and angina pectoris before the onset of RA symptoms in 2 large population‐based case–control studies. Patients with newly diagnosed RA according to the criteria of the American College of Rheumatology were included as cases. We used data from the Swedish Early Arthritis Register study and the Swedish Epidemiologic Investigation of Rheumatoid Arthritis case–control study and from general population controls. Information on IHD, MI, and angina pectoris was obtained from the nationwide Hospital Discharge Register and from self reports. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) to compare the prevalence of a history of IHD/MI/angina pectoris among patients with RA with that among population controls.

Results

We could not detect any increased occurrence of IHD, MI, or angina pectoris before the onset of symptoms of RA, regardless of whether data on IHD were obtained from the Hospital Discharge Register or were self reported. As detected in the Hospital Discharge Register, the OR for IHD overall was 1.0 (95% CI 0.9–1.1), the OR for MI was 1.0 (95% CI 0.9–1.1), and the OR for angina pectoris was 1.0 (95% CI 0.9–1.2).

Conclusion

Shared risk factors or susceptibilities for RA and IHD are likely to contribute less than RA‐related factors to the increased occurrence of IHD in patients with manifest RA. Nonetheless, the existence of shared factors associated with longer latency until the occurrence of IHD cannot be excluded.
Mechanical injury potentiates proteoglycan catabolism induced by interleukin‐6 with soluble interleukin‐6 receptor and tumor necrosis factor α in immature bovine and adult human articular cartilage
Authors: Sui Yihong , Lee Jennifer H. , DiMicco Michael A. , Vanderploeg Eric J. , Blake Simon M. , Hung Han‐Hwa , Plaas Anna H. K. , James Ian E. , Song Xiao‐Yu , Lark Michael W. , Grodzinsky Alan J.
Published: September 2009

Objective

Traumatic joint injury can damage cartilage and release inflammatory cytokines from adjacent joint tissue. The present study was undertaken to study the combined effects of compression injury, tumor necrosis factor α (TNFα), and interleukin‐6 (IL‐6) and its soluble receptor (sIL‐6R) on immature bovine and adult human knee and ankle cartilage, using an in vitro model, and to test the hypothesis that endogenous IL‐6 plays a role in proteoglycan loss caused by a combination of injury and TNFα.

Methods

Injured or uninjured cartilage disks were incubated with or without TNFα and/or IL‐6/sIL‐6R. Additional samples were preincubated with an IL‐6–blocking antibody Fab fragment and subjected to injury and TNFα treatment. Treatment effects were assessed by histologic analysis, measurement of glycosaminoglycan (GAG) loss, Western blot to determine proteoglycan degradation, zymography, radiolabeling to determine chondrocyte biosynthesis, and Western blot and enzyme‐linked immunosorbent assay to determine chondrocyte production of IL‐6.

Results

In bovine cartilage samples, injury combined with TNFα and IL‐6/sIL‐6R exposure caused the most severe GAG loss. Findings in human knee and ankle cartilage were strikingly similar to those in bovine samples, although in human ankle tissue, the GAG loss was less severe than that observed in human knee tissue. Without exogenous IL‐6/sIL‐6R, injury plus TNFα exposure up‐regulated chondrocyte production of IL‐6, but incubation with the IL‐6–blocking Fab significantly reduced proteoglycan degradation.

Conclusion

Our findings indicate that mechanical injury potentiates the catabolic effects of TNFα and IL‐6/sIL‐6R in causing proteoglycan degradation in human and bovine cartilage. The temporal and spatial evolution of degradation suggests the importance of transport of biomolecules, which may be altered by overload injury. The catabolic effects of injury plus TNFα appeared partly due to endogenous IL‐6, since GAG loss was partially abrogated by an IL‐6–blocking Fab.
Scavenger receptor class A type I/II determines matrix metalloproteinase–mediated cartilage destruction and chondrocyte death in antigen‐induced arthritis
Authors: van Lent P. L. E. M. , Hofkens W. , Blom A. B. , Grevers L. , Sloetjes A. , Takahashi N. , van Tits L. J. , Vogl T. , Roth J. , de Winther M. P. , van den Berg W. B.
Published: September 2009

Objective

Scavenger receptor class A type I (SR‐AI) and SR‐AII are expressed by macrophages in particular and bind and internalize a broad range of molecules (including endotoxins, apoptotic bodies, and oxidized low‐density lipoprotein). This study was undertaken to investigate the role of SR‐AI/II in mediating severe cartilage destruction in antigen‐induced arthritis (AIA).

Methods

AIA was induced in the knee joints of SR‐AI/II−/− mice and wild‐type (WT) controls. Joint inflammation and cartilage destruction (chondrocyte death) were measured by examining the histology of total knee joints. Matrix metalloproteinase (MMP)–mediated neoepitopes were measured by immunolocalization using anti‐VDIPEN antibodies and chondrocyte activation with anti‐S100A8 antibodies. Messenger RNA (mRNA) levels were determined in inflamed synovium using microarray analysis and quantitative reverse transcriptase–polymerase chain reaction. In synovial washouts, cytokines (interleukin‐1β [IL‐1β], IL‐10, and tumor necrosis factor α) and S100A8/S100A9 were measured using Luminex and enzyme‐linked immunosorbent assay.

Results

Levels of SR‐AI/II mRNA were strongly elevated in inflamed synovium in AIA. On days 2, 8, and 14 after AIA induction, joint inflammation (exudates/infiltrate) was similar between the 2 groups. In WT mice, severe cartilage destruction was found in multiple cartilage surfaces of the inflamed knee joint on day 14 after AIA induction. MMP‐mediated matrix destruction ranged between 40% and 60%, and chondrocyte death was prominent in 40–75% of the cartilage surfaces. In striking contrast, in SR‐AI/II−/− mice, despite comparable joint inflammation, pronounced cartilage destruction was almost completely absent. Levels of IL‐1β and S100A8/S100A9 were significantly lower on days 7 and 14 after AIA induction, but levels of mRNA for various MMPs (MMP‐2, MMP‐3, MMP‐9, and MMP‐13) were comparable.

Conclusion

Our findings indicate that SR‐AI and SR‐AII are crucial receptors involved in mediating severe cartilage destruction in AIA.