Prevalence of abnormalities in knees detected by MRI in adults without knee osteoarthritis: population based observational study (Framingham Osteoarthritis Study)

Objective: To examine use of magnetic resonance imaging (MRI) of knees with no radiographic evidence of osteoarthritis to determine the prevalence of structural lesions associated with osteoarthritis and their relation to age, sex, and obesity. Design: Population based observational study. Setting: Community cohort in Framingham, MA, United States (Framingham osteoarthritis study). Participants: 710 people aged >50 who had no radiographic evidence of knee osteoarthritis (Kellgren-Lawrence grade 0) and who underwent MRI of the knee. Main outcome measures: Prevalence of MRI findings that are suggestive of knee osteoarthritis (osteophytes, cartilage damage, bone marrow lesions, subchondral cysts, meniscal lesions, synovitis, attrition, and ligamentous lesions) in all participants and after stratification by age, sex, body mass index (BMI), and the presence or absence of knee pain. Pain was assessed by three different questions and also by WOMAC questionnaire. Results: Of the 710 participants, 393 (55%) were women, 660 (93%) were white, and 206 (29%) had knee pain in the past month. The mean age was 62.3 years and mean BMI was 27.9. Prevalence of “any abnormality” was 89% (631/710) overall. Osteophytes were the most common abnormality among all participants (74%, 524/710), followed by cartilage damage (69%, 492/710) and bone marrow lesions (52%, 371/710). The higher the age, the higher the prevalence of all types of abnormalities detectable by MRI. There were no significant differences in the prevalence of any of the features between BMI groups. The prevalence of at least one type of pathology (“any abnormality”) was high in both painful (90-97%, depending on pain definition) and painless (86-88%) knees. Conclusions: MRI shows lesions in the tibiofemoral joint in most middle aged and elderly people in whom knee radiographs do not show any features of osteoarthritis, regardless of pain

Hormone Therapy and the Risk of Breast Cancer in BRCA1 Mutation Carriers

Background: Hormone therapy (HT) is commonly given to women to alleviate the climacteric symptoms associated with menopause. There is concern that this treatment may increase the risk of breast cancer. The potential association of HT and breast cancer risk is of particular interest to women who carry a mutation in BRCA1 because they face a high lifetime risk of breast cancer and because many of these women take HT after undergoing prophylactic surgical oophorectomy at a young age. Methods: We conducted a matched case-control study of 472 postmenopausal women with a BRCA1 mutation to examine whether or not the use of HT is associated with subsequent risk of breast cancer. Breast cancer case patients and control subjects were matched with respect to age, age at menopause, and type of menopause (surgical or natural). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with conditional logistic regression. Statistical tests were two-sided. Results: In this group of BRCA1 mutation carriers, the adjusted OR for breast cancer associated with ever use of HT compared with never use was 0.58 (95% CI = 0.35 to 0.96; P =. 03). In analyses by type of HT, an inverse association with breast cancer risk was observed with use of estrogen only (OR = 0.51, 95% CI = 0.27 to 0.98; P =. 04); the association with use of estrogen plus progesterone was not statistically significant (OR = 0.66, 95% CI = 0.34 to 1.27; P =. 21). Conclusion: Among postmenopausal women with a BRCA1 mutation, HT use was not associated with increased risk of breast cancer; indeed, in this population, it was associated with a decreased risk

Knee osteoarthritis patients with more subchondral cysts have altered tibial subchondral bone mineral density

Background: Subchondral bone cysts are a widely observed, but poorly understood, feature in patients with knee osteoarthritis (OA). Clinical quantitative computed tomography (QCT) has the potential to characterize cysts in vivo but it is unclear which specific cyst parameters (e.g., number, size) are associated with clinical signs of OA, such as disease severity or pain. The objective of this study was to use QCT-based image-processing techniques to characterize subchondral tibial cysts in patients with knee OA and to explore relationships between proximal tibial subchondral cyst parameters and subchondral bone density as well as clinical characteristics of OA (alignment, joint space narrowing (JSN), OA severity, pain) in patients with knee OA. Methods: The preoperative knee of 42 knee arthroplasty patients was scanned using QCT. Patient characteristics were obtained, including OA severity, knee pain, JSN, and alignment. We used 3D image processing techniques to obtain cyst parameters including: cyst number, cyst number per proximal tibial volume, cyst volume per proximal tibial volume, as well as maximum and average cyst volume across the proximal tibia, as well as regional bone mineral density (BMD) excluding cysts. We used Spearman’s correlation coefficients to explore associations between patient characteristics and cyst parameters. Results: At both the medial and lateral compartments of the proximal tibia, greater cyst number and volume were associated with higher BMD. At the lateral region, cyst number and volume were also associated with lateral OA severity, lateral JSN, alignment and sex. Pain was not associated with any cyst parameters at any region. Conclusion: Cyst number and volume were associated with BMD at both the medial and lateral compartments. Lateral cyst number and volume were also associated with joint alignment, OA severity, JSN and sex. This is the first study to use clinical QCT to explore subchondral tibial cysts in patients with knee OA and provides further evidence of the relationships between subchondral cysts and clinical OA characteristics.Other UBCNon UBCReviewedFacult

Proximal tibial trabecular bone mineral density is related to pain in patients with osteoarthritis

Background: Our objective was to examine the relationships between proximal tibial trabecular (epiphyseal and metaphyseal) bone mineral density (BMD) and osteoarthritis (OA)-related pain in patients with severe knee OA. Methods: The knee was scanned preoperatively using quantitative computed tomography (QCT) in 42 patients undergoing knee arthroplasty. OA severity was classified using radiographic Kellgren-Lawrence scoring and pain was measured using the pain subsection of the Western Ontario and McMaster Universities Arthritis Index (WOMAC). We used three-dimensional image processing techniques to assess tibial epiphyseal trabecular BMD between the epiphyseal line and 7.5 mm from the subchondral surface and tibial metaphyseal trabecular BMD 10 mm distal from the epiphyseal line. Regional analysis included the total epiphyseal and metaphyseal region, and the medial and lateral epiphyseal compartments. The association between total WOMAC pain scores and BMD measurements was assessed using hierarchical multiple regression with age, sex, and body mass index (BMI) as covariates. Statistical significance was set at p < 0.05. Results: Total WOMAC pain was associated with total epiphyseal BMD adjusted for age, sex, and BMI (p = 0.013) and total metaphyseal BMD (p = 0.017). Regionally, total WOMAC pain was associated with medial epiphyseal BMD adjusted for age, sex, and BMI (p = 0.006). Conclusion: These findings suggest that low proximal tibial trabecular BMD may have a role in OA-related pain pathogenesis.Other UBCNon UBCReviewedFacult

Hepatocyte Produced Matrix Metalloproteinases Are Regulated by CD147 in Liver Fibrogenesis

<div><p>Background</p><p>The classical paradigm of liver injury asserts that hepatic stellate cells (HSC) produce, remodel and turnover the abnormal extracellular matrix (ECM) of fibrosis via matrix metalloproteinases (MMPs). In extrahepatic tissues MMP production is regulated by a number of mechanisms including expression of the glycoprotein CD147. Previously, we have shown that CD147 is expressed on hepatocytes but not within the fibrotic septa in cirrhosis <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090571#pone.0090571-Shackel1" target="_blank">[1]</a>. Therefore, we investigated if hepatocytes produce MMPs, regulated by CD147, which are capable of remodelling fibrotic ECM independent of the HSC.</p><p>Methods</p><p>Non-diseased, fibrotic and cirrhotic livers were examined for MMP activity and markers of fibrosis in humans and mice. CD147 expression and MMP activity were co-localised by <i>in-situ</i> zymography. The role of CD147 was studied <i>in-vitro</i> with siRNA to CD147 in hepatocytes and <i>in-vivo</i> in mice with CCl₄ induced liver injury using <b>ã</b>CD147 antibody intervention.</p><p>Results</p><p>In liver fibrosis in both human and mouse tissue MMP expression and activity (MMP-2, -9, -13 and -14) increased with progressive injury and localised to hepatocytes. Additionally, as expected, MMPs were abundantly expressed by activated HSC. Further, with progressive fibrosis there was expression of CD147, which localised to hepatocytes but not to HSC. Functionally significant <i>in-vitro</i> regulation of hepatocyte MMP production by CD147 was demonstrated using siRNA to CD147 that decreased hepatocyte MMP-2 and -9 expression/activity. Further, <i>in-vivo</i> α-CD147 antibody intervention decreased liver MMP-2, -9, -13, -14, TGF-β and α-SMA expression in CCl₄ treated mice compared to controls.</p><p>Conclusion</p><p>We have shown that hepatocytes produce active MMPs and that the glycoprotein CD147 regulates hepatocyte MMP expression. Targeting CD147 regulates hepatocyte MMP production both <i>in-vitro</i> and <i>in-vivo</i>, with the net result being reduced fibrotic matrix turnover <i>in-vivo</i>. Therefore, CD147 regulation of hepatocyte MMP is a novel pathway that could be targeted by future anti-fibrogenic agents.</p></div

Expression of MMP mRNA in human liver.

<p>Quantitative PCR on whole liver tissue, non-diseased and HCV cirrhosis, of MMP-1, MMP-2, MMP-9 and MMP-14 mRNA (n = 4 per group). The expression of MMPs measured was significantly increased in cirrhosis compared to non-diseased controls, *p<0.05.</p