Osteoarthritis and Cartilage

MRI of weight bearing and movement

L.M. Shapiro, G.E. Gold — 2011-12-22

Summary: Conventional, static magnetic resonance imaging (MRI) is able to provide a vast amount of information regarding the anatomy and pathology of the musculoskeletal system. However, patients, especially those whose pain is position dependent or elucidated by movement, may benefit from more advanced imaging techniques that allow for the acquisition of functional information. This manuscript reviews a variety of advancements in MRI techniques that are used to image the musculoskeletal system dynamically, while in motion or under load. The methodologies, advantages and drawbacks of stress MRI, cine-phase contrast MRI and real-time MRI are discussed as each has helped to advance the field by providing a scientific basis for understanding normal and pathological musculoskeletal anatomy and function. Advancements in dynamic MR imaging will certainly lead to improvements in the understanding, prevention, diagnosis and treatment of musculoskeletal disorders. It is difficult to anticipate that dynamic MRI will replace conventional MRI, however, dynamic MRI may provide additional valuable information to findings of conventional MRI.

Relationship between insulin-like growth factor-1 and radiographic disease in patients with primary osteoarthritis: a systematic review

2011-12-26

Summary: Objective: To evaluate the association between radiographic osteoarthritis (OA) and either serum insulin-like growth factor-1 (IGF-1) levels or IGF-1 gene polymorphisms in patients with primary OA.Methods: We conducted a systematic review of reported associations between circulating IGF-1 and/or IGF-1 gene polymorphisms and radiographic OA. Studies were eligible when: (1) investigating serum IGF-1 and/or IGF-1 gene polymorphisms in relation to prevalent or incident radiographic OA; (2) written in English; (3) full-text article or abstract; (4) patients had primary OA in knee, hip, hand or spine; (5) longitudinal, case-control or cross-sectional design. Quality assessment was done using a standardized criteria set. Best-evidence synthesis was performed based on guidelines on systematic review from the Cochrane Collaboration Back Review Group, using five evidence levels: strong, moderate, limited, conflicting and no evidence.Results: We included 11 studies with more than 3000 primary OA cases. Data on the relationship between serum IGF-1 and radiographic OA were inconsistent. Adjustment for body mass index (BMI) was often omitted. Of four high-quality studies, three studies reported no association, one study found significantly higher IGF-1 levels in OA patients compared to controls. Patients with IGF-1 gene promoter polymorphisms and a genetic variation at the IGF-1R locus had an increased OA prevalence compared to controls.Conclusions: Observational data showed no association between serum IGF-1 and occurrence of radiographic OA (moderate level of evidence), and a positive relationship between IGF-1 gene polymorphisms and radiographic OA (moderate level of evidence); however the confounding effect of BMI was insufficiently addressed. Future well-designed prospective studies should further elaborate the role of the complex GH/IGF-1 system in primary OA.

Patient acceptable symptom state and OMERACT–OARSI set of responder criteria in joint replacement. Identification of cut-off values

2011-12-22

Summary: Objective: To identify new cut-off values beyond which patients can be considered as satisfied or as responders through patient acceptable symptom state (PASS) and OMERACT–OARSI (Outcome Measures in Rheumatology–Osteoarthritis Research Society International) set of responder criteria in total joint replacement.Methods: Secondary analysis of a 1-year prospective multicenter study of 861 patients, 510 with total knee replacement (TKR) and 351 with total hip prosthesis (THR). Pain and function data were collected by the reverse scoring option of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). PASS values were identified with the 25th centile estimation using an anchoring question about satisfaction with actual symptoms. OMERACT–OARSI set of responder criteria was based on a combination of absolute and relative change of pain, function and global patient’s assessment. Receiver operating characteristic (ROC) analysis was used as a complementary approach.Results: The values for PASS were about 80 and 69 for pain and function in THR, while these values were 80 and 68 when using OMERACT–OARSI criteria. Regarding TKR, PASS values were about 75 and 67 in pain and function with both criteria. ROC values were slightly lower in all cases. PASS and OMERACT–OARSI values varied moderately across tertiles of baseline severity.Conclusion: With the provided data we can establish when a patient can be considered as satisfied/responder in joint replacement. The scores achieved at 1 year were very similar according to both criteria.

OARSI–OMERACT initiative: defining thresholds for symptomatic severity and structural changes in disease modifying osteoarthritis drug (DMOAD) clinical trials

2012-01-05

Summary: Objective: Total joint replacement has been proposed as an endpoint in disease modifying osteoarthritis drug (DMOAD) randomized clinical trials (RCTs); however, disparities have generated concerns regarding this outcome. A combined Osteoarthritis Research Society International (OARSI)/Outcome Measures in Rheumatology (OMERACT) initiative was launched in 2004 to develop a composite index [‘virtual total joint replacement’ (VJR)] as a surrogate outcome for osteoarthritis (OA) progression in DMOAD RCTs. Our objective was to evaluate the prevalence of patients fulfilling different thresholds of sustained pain, reduced function, and X-ray change in existing DMOAD RCTs.Design: Post hoc analysis of summary data from the placebo arm of eight DMOAD RCTs.Results: Eight OA RCTs representing 1379 patients were included. Pain was assessed by WOMAC and/or VAS and function by WOMAC and/or Lequesne. Among six knee and two hip studies, 248 (22%) and 132 (51%) patients respectively had X-ray progression [decrease joint space width (JSW) ≥0.5 mm]. The prevalence of patients fulfilling clinical and radiographic criteria was highest (n = 163, 12%) in the least stringent scenario (pain + function ≥80 at ≥2 visits); with few patients (n = 129, 2%) in the most stringent scenario (pain + function ≥80 at ≥4 visits). Using these prevalence data, a sample size of 352–2144 per group would be needed to demonstrate a 50% difference between groups.Conclusions: The prevalence of patients with sustained symptomatic OA of at least a moderate degree with X-ray progression is low. Even using lenient criteria to define VJR, large patient numbers would be required to detect differences between groups in DMOAD RCTs. Investigation of the optimal cutoff threshold and combination of symptoms and radiographic change should be pursued.

The assessment of persistent pain after joint replacement

V. Wylde, A. Jeffery, P. Dieppe, R. Gooberman-Hill — 2011-12-22

Summary: This study used ‘think aloud’ to explore issues around using a standardised questionnaire to assess persistent pain after joint replacement. Twenty participants with moderate–extreme persistent pain in their replaced hip or knee completed the Chronic Pain Grade (CPG) while ‘thinking aloud’. The interviews were audio-recorded, transcribed and analysed using thematic analysis. Completion of the CPG by patients was influenced by four issues: challenges with the question wording or response options on the CPG items; the fluctuating nature of pain and functional limitations; the need to account for co-morbidities and pain elsewhere; and adjustment to pain. These issues reflect those that have arisen previously in patients with musculoskeletal pain, and need to be considered when assessing persistent joint pain, both before and after joint replacement.

Synovial fluid CD34− CD44+ CD90+ mesenchymal stem cell levels are associated with the severity of primary knee osteoarthritis

D.-H. Lee, C.H. Sonn, S.-B. Han, Y. Oh, K.-M. Lee, S.-H. Lee — 2011-12-19

Summary: To the best of our knowledge, no reports have directly compared synovial fluid (SF)- and synovial membrane (SM)-derived mesenchymal stem cells (MSCs) from primary knee osteoarthritis patients in terms of MSC proportion, either immediately after isolation or during culture. Any possible correlation between SM- and SF-MSC purity and osteoarthritis severity, also remains unclear. We therefore assessed quantitative and phenotypic differences in MSCs isolated from SF and SM. We also evaluated the correlation between sample MSC purity, and disease severity, in patients with osteoarthritis. The main result of the current study was that the mean SF-MSC proportion at passage 0 was negatively correlated with Kellgren–Lawrence (KL) grade (r = −0.565, P = 0.002). In addition, KL grade was a only significant independent negative predictor of SF-MSC proportion at passage 0 (β = −0.356, P = 0.039). Conclusively, the proportion of SF-MSCs in fresh samples, evaluated at the single cell level, was inversely correlated with osteoarthritis severity.

Morphological changes of the lateral meniscus in end-stage lateral compartment osteoarthritis of the knee

2011-12-12

Summary: Objective: The aim of this study was to evaluate the morphological changes of the lateral meniscus in end-stage lateral compartment osteoarthritis (OA) of the knee.Methods: One hundred fifty-eight knee joints from 133 patients that subsequently underwent total knee joint arthroplasty from January 2008 to December 2009 were enrolled. There were 26 men and 107 women. Their ages ranged from 56 to 81 (mean 67.4 ± 6.5 years). All study participants had complete obliteration of the lateral joint space identified by weight-bearing radiography. Meniscal position was assessed by measuring meniscal subluxation and meniscal height. The meniscal morphology was assessed using a modification of the whole-organ magnetic resonance imaging score (WORMS). The frequency of different meniscal morphology and their respective positions was calculated.Results: The predominant type (42.4%, 53.8% and 52.5% in the anterior horn, mid-body and posterior horn, respectively) of abnormal meniscal morphology was a complete maceration/destruction or complete resection. The anterior horn of non-macerated lateral meniscus was more subluxed than that of the non-macerated medial meniscus in patients with lateral OA.Conclusion: This study suggests that the lateral meniscus in persons with end-stage lateral OA are mostly macerated or destroyed. Also, unlike isolated end-staged medial compartment OA, the anterior horn of the lateral meniscus in isolated end-stage lateral OA is commonly affected.

Diffusion of Gd-DTPA2− into articular cartilage

E.-N. Salo, M.J. Nissi, K.A.M. Kulmala, V. Tiitu, J. Töyräs, M.T. Nieminen — 2011-12-26

Summary: Objectives: The delayed Gadolinium-Enhanced MRI of Cartilage (dGEMRIC) technique is a method proposed for non-invasive measurement of cartilage glycosaminoglycan (GAG) content. In this method, gadopentetate (Gd-DTPA2−) is assumed to distribute in cartilage in inverse relation to the GAG distribution, thus allowing quantification of the GAG content. For accurate GAG quantification, the kinetics of Gd-DTPA2− in articular cartilage is of critical importance. However, the diffusion of Gd-DTPA2− has not been systematically studied over long time periods using MRI-feasible gadopentetate concentrations. Thus, the present study aims to investigate the diffusion of gadopentetate into cartilage in vitro in intact and enzymatically degraded cartilage.Methods: The diffusion of gadopentetate into bovine articular cartilage was investigated at 9.4T over 18-h time period using repeated T1 measurements in two models, (1) comparing intact and trypsin-treated tissue and (2) assessing the effect of penetration direction. The diffusion process was further assessed by determining the gadopentetate flux and diffusivity. The results were compared with histological and biochemical reference methods.Results and conclusions: The results revealed that passive diffusion of Gd-DTPA2− was significantly slower than previously assumed, leading to overestimation of the GAG content at equilibrating times of few hours. Moreover, Gd-DTPA2− distribution was found to depend not only on GAG content, but also on collagen content and diffusion direction. Interestingly, the dGEMRIC technique was found to be most sensitive to cartilage degradation in the early stages of diffusion process, suggesting that full equilibrium between gadopentetate and cartilage may not be required in order to detect cartilage degeneration.

A potential role of chondroitin sulfate on bone in osteoarthritis: inhibition of prostaglandin E2 and matrix metalloproteinases synthesis in interleukin-1β- stimulated osteoblasts

2011-12-26

Summary: Objectives: To determine the effect of chondroitin sulfate (CS) on inflammatory mediators and proteolytic enzymes induced by interleukin-1β (IL-1β) and related to cartilage catabolism in murine osteoblasts.Design: Osteoblasts were obtained by enzymatic digestion of calvaria from Swiss mice and cultured for 3weeks as a primary culture. Cells were then stimulated with IL-1β (1 or 10ng/ml). CS-treated osteoblasts were incubated with 100μg/ml of CS during the last week of culture w/o IL-1β for the last 24h. Expressions of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), 15-PG dehydrogenase (15-PGDH), matrix metalloproteinases-3 and -13 (MMP-3 and -13), osteoprotegerin (OPG) and receptor activator of nuclear factor-kappa B ligand (RANKL) were determined by real-time polymerase chain reaction (PCR). PGE2, MMP-3 and MMP-13 release were assessed in the medium by enzyme-linked immunosorbent assay or western-blotting.Results: IL-1β increased COX-2, mPGES-1, MMP-3, MMP-13, RANKL expressions, decreased 15-PGDH expression, and increased PGE2, MMP-3 and MMP-13 release. Interestingly, 7days of CS treatment significantly counteracted IL-1β-induced expression of COX-2 (−62%, P<0.001), mPGES-1 (−63%, P<0.001), MMP-3 (−39%, P=0.08), MMP-13 (−60%, P<0.001) and RANKL (−84%, P<0.001). Accordingly, IL-1β-induced PGE2, MMP-3 and MMP-13 releases were inhibited by 86% (P<0.001), 58%(P<0.001) and 38% (P<0.01) respectively.Conclusions: In conclusion, our data demonstrate that, in an inflammatory context, CS inhibits the production of PGE2 and MMPs. Since CS has previously been shown to counteract the production of these mediators in chondrocytes, we speculate that the beneficial effect of CS in Osteoarthritis (OA) could not only be due to its action on cartilage but also on subchondral bone.

Mice over-expressing salmon calcitonin have strongly attenuated osteoarthritic histopathological changes after destabilization of the medial meniscus

2011-12-14

Summary: Objective: Calcitonin is well-known for its inhibitory actions on bone-resorbing osteoclasts and recently potential beneficial effects on cartilage were shown. We investigated effects of salmon calcitonin (sCT) on the articular cartilage and bone, after destabilization of the medial meniscus (DMM) in normal and sCT over-expressing mice.Design: Bone phenotype of transgenic (TG) C57Bl/6 mice over-expressing sCT at 6months and 12months was investigated by (1) serum osteocalcin and urinary deoxypyridinoline and (2) dynamic and normal histomorphometry of vertebrae bodies. In subsequent evaluation of cartilage and subchondral bone changes, 44 10-week old TG or wild-type (WT) mice were randomized into four groups and subjected to DMM or sham-operations. After 7weeks animals were sacrificed, and knee joints were isolated for histological analysis.Results: Trabecular bone volume (BV/TV) increased 150% after 6months and 300% after 12months in sCT-expressing mice when compared to WT controls (P<0.05). Osteoblast number, bone formation rate and osteocalcin measurements were not affected in TG mice over-expressing sCT. In WT animals, a 5-fold increase in the quantitative erosion index was observed after DMM, and the semi-quantitative OARSI score showed over 400% (P<0.001) increase, compared to sham-operated WT mice. DMM-operated TG mice were protected against cartilage erosion and showed a 65% and 64% (P<0.001) reduction, respectively, for the two histopathological evaluation methods.Conclusions: sCT over-expressing mice had higher bone volume, and were protected against cartilage erosion. These data suggest that increased levels of sCT may hamper the pathogenesis of osteoarthritis (OA). However more studies are necessary to confirm these preliminary results.

Reduced chondrocyte proliferation, earlier cell cycle exit and increased apoptosis in neuronal nitric oxide synthase-deficient mice

Q. Yan, Q. Feng, F. Beier — 2011-12-23

Summary: Objective: Nitric oxide (NO) has been implicated in the local regulation of bone metabolism. However, the contribution made by specific nitric oxide synthase (NOS) enzymes to skeletal development is unclear. The objective of this study was to examine the effects of inactivation of neuronal nitric oxide synthase (nNOS) on cartilage development in mice.Design: Mice carrying a null mutation in the nNOS gene were used to address our objectives. Histological staining, immunohistochemistry and in situ analyses were employed along with real-time reverse transcriptase - polymerase chain reaction (RT-PCR).Results: nNOS-null mice show transient growth retardation and shorter long bones. nNOS-deficient growth plates show a reduction in replicating cells. Reduced chondrocyte numbers may in part be due to slower cell cycle progression and premature cell cycle exit caused by decreased cyclin D1 and increased p57 expression in mutants. In addition, apoptosis was increased as shown by increased cleaved-caspase 3 staining in hypertrophic chondrocytes in mutants. Real-time PCR demonstrated that expression of early chondrocyte markers such as Sox genes was reduced in mutant mice, while expression of prehypertrophic markers such as RORα was increased. Histological sections also demonstrated thinner cortical bone, fewer trabeculae and reduced mineralization in mutant mice.Conclusions: These data identify an important role of nNOS in chondrocyte proliferation and endochondral bone growth and demonstrate that nNOS coordinates cell cycle exit and chondrocyte differentiation in cartilage development.

Depletion of primary cilia in articular chondrocytes results in reduced Gli3 repressor to activator ratio, increased Hedgehog signaling, and symptoms of early osteoarthritis

C.-F. Chang, G. Ramaswamy, R. Serra — 2011-12-19

Summary: Objective: Primary cilia are present in almost every cell type including chondrocytes. Studies have shown that defects in primary cilia result in skeletal dysplasia. The purpose of this study was to understand how loss of primary cilia affects articular cartilage.Design: Ift88 encodes a protein that is required for intraflagellar transport and formation of primary cilia. In this study, we used Col2aCre;Ift88fl/fl transgenic mice in which primary cilia were deleted in chondrocytes. Col2aCre;Ift88fl/fl articular cartilage was characterized by histological staining, real time RT-PCR, and microindentation. Hedgehog (Hh) signaling was measured by expression of Ptch1 and Gli1 mRNA. The levels of Gli3 proteins were determined by western blot.Results: Col2aCre;Ift88fl/fl articular cartilage was thicker and had increased cell density, likely due to decreased apoptosis during cartilage remodeling. Mutant articular cartilage also showed increased expression of osteoarthritis (OA) markers including Mmp13, Adamts5, ColX, and Runx2. OA was also evident by reduced stiffness in mutant cartilage as measured by microindentation. Up-regulation of Hh signaling, which has been associated with OA, was present in mutant articular cartilage as measured by expression of Ptch1 and Gli1. Col2aCre;Ift88fl/fl cartilage also demonstrated reduced Gli3 repressor to activator ratio.Conclusion: Our results indicate that primary cilia are required for normal development and maintenance of articular cartilage. It was shown that primary cilia are required for processing full length Gli3 to the truncated repressor form. We propose that OA symptoms in Col2aCre;Ift88fl/fl cartilage are due to reduced Hh signal repression by Gli3.

Molecular differentiation between osteophytic and articular cartilage – clues for a transient and permanent chondrocyte phenotype

2012-01-04

Summary: Objective: To identify the molecular differences between the transient and permanent chondrocyte phenotype in osteophytic and articular cartilage.Methods: Total RNA was isolated from the cartilaginous layer of osteophytes and from intact articular cartilage from knee joints of 15 adult human donors and subjected to cDNA microarray analysis. The differential expression of relevant genes between these two cartilaginous tissues was additionally validated by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and by immunohistochemistry.Results: Among 47,000 screened transcripts, 600 transcripts were differentially expressed between osteophytic and articular chondrocytes. Osteophytic chondrocytes were characterized by increased expression of genes involved in the endochondral ossification process [bone gamma-carboxyglutamate protein/osteocalcin (BGLAP), bone morphogenetic protein-8B (BMP8B), collagen type I, alpha 2 (COL1A2), sclerostin (SOST), growth arrest and DNA damage-induced gene 45ß (GADD45ß), runt-related transcription factor 2 (RUNX2)], and genes encoding tissue remodeling enzymes [matrix metallopeptidase (MMP)9, 13, hyaluronan synthase 1 (HAS1)]. Articular chondrocytes expressed increased transcript levels of antagonists and inhibitors of the BMP- and Wnt-signaling pathways [Gremlin-1 (GREM1), frizzled-related protein (FRZB), WNT1 inducible signaling pathway protein-3 (WISP3)], as well as factors that inhibit terminal chondrocyte differentiation and endochondral bone formation [parathyroid hormone-like hormone (PTHLH), sex-determining region Y-box 9 (SOX9), stanniocalcin-2 (STC2), S100 calcium binding protein A1 (S100A1), S100 calcium binding protein B (S100B)].Immunohistochemistry of tissue sections for GREM1 and BGLAP, the two most prominent differentially expressed genes, confirmed selective detection of GREM1 in articular chondrocytes and that of BGLAP in osteophytic chondrocytes and bone.Conclusions: Osteophytic and articular chondrocytes significantly differ in their gene expression pattern. In articular cartilage, a prominent expression of antagonists inhibiting the BMP- and Wnt-pathway may serve to lock and stabilize the permanent chondrocyte phenotype and thus prevent their terminal differentiation. In contrast, osteophytic chondrocytes express genes with roles in the endochondral ossification process, which may account for their transient phenotype.

An experimental study on costal osteochondral graft

2012-01-03

Summary: Objective: To investigate usefulness of osteochondral grafting from the costo-osteochondral junction as a repair technique for articular cartilage defects histologic and biochemical analysis of grafted cartilage in rabbit knees was evaluated up to 48weeks after transplantation.Methods: Twenty New Zealand White rabbits were used. A costal osteochondral plug was harvested from a middle rib. After trimming, it was transplanted into a cylindrical osteochondral 2.5mm diameter and 5mm deep defect created in the knee. The animals were sacrificed at 6, 12, 24, and 48weeks after transplantation. Defect sites were inspected macroscopically, and then by light microscopy. Samples were evaluated for cell viability using a fluorescent in situ double-staining protocol with confocal laser microscopic analysis. Samples were also processed to assess type I & II collagen and aggrecan mRNA expression using reverse transcription-polymerase chain reaction (RT-PCR).Results: Histologically, bone union was achieved in all plugs. Confocal microscopic analysis revealed chondrocyte viability in the 48-week grafts; the distribution of chondrocytes was similar to surrounding articular cartilage. The expression of type II collagen and aggrecan mRNA in the grafted cartilage was consistent with normal articular cartilage and normal costal cartilage. These results were observed over 6–48weeks.Conclusions: Our study revealed that chondrocytes in the grafted cartilage were viable at least up to 48weeks and that mRNA expression of type II collagen and aggrecan was also similar to that of normal articular cartilage. These results suggest that costal osteochondral grafting can be a useful alternative in the treatment of osteochondral defects.

Spin–lattice relaxation rates and water content of freeze-dried articular cartilage

2012-01-03

Summary: Objective: Nuclear magnetic resonance (NMR) spin–lattice relaxation rates were measured in bovine and porcine articular cartilage as a function of water content.Methods: Water content was varied by freeze-drying samples for short periods of time (up to 15min). The samples were weighed at all stages of drying so that water content could be quantified. Spin–lattice relaxation rates were measured using magnetic resonance imaging (MRI).Results: Linear correlations were observed between relaxation rate and two measures of inverse water content: (1) solid-to-water ratio (), expressed as a ratio of the mass of the solid component of the cartilage (ms) and the mass of water at each freeze-drying time point (mw), and (2) a ratio of the total mass of the fully-hydrated cartilage and mw (1/w). These correlations did not appear significantly different for the bovine and porcine data. However, fitting the data to a piecewise-linear model revealed differences between these two species. We interpret the first two segments of the piecewise model as the depletion of different water phases but conjecture that the third segment is partially caused by changes in relaxation rates as a result of a reduction in macromolecular mobilities.Conclusions: Whilst we can produce linear correlations which broadly describe the dependence of the measured spin–lattice relaxation rate on (inverse) water content, the linear model seems to obscure a more complicated relationship which potentially provides us with more information about the structure of articular cartilage and its extracellular water.