Bone marrow lesion is associated with disability for activities of daily living in patients with early stage knee osteoarthritis.

Osteoarthritis of the knee (knee OA) induces pain, loss of mobility and diminished activities of daily living (ADL). Although an understanding of the pathophysiology of early stage knee OA has been developed, the structural changes associated with disability for ADL in early stage knee OA are still unclear. The aim of the present study was to examine magnetic resonance imaging (MRI)-detected changes associated with disability for ADL in patients with early stage knee OA. One hundred and thirty-two patients with early stage medial knee OA (Kellgren-Lawrence grade ≤ 2) who first visited the outpatient clinic at our university hospital were included. They were also examined by 3.0-Tesla knee MRI. The OA-associated structural changes were scored using the Whole-Organ Magnetic Resonance Imaging Score (WORMS), and clinical manifestations were evaluated by the Japanese Knee Osteoarthritis Measure (JKOM). Median quartile regression was used for the analysis. Cartilage lesion, subchondral bone attrition and osteophytes were observed in all patients. Bone marrow lesions (BMLs) and synovitis were observed in 60% and 55% of the patients, respectively. Subchondral cysts and ligament changes were observed in 6% and 17% of the patients, respectively. Pain severity of the patients was associated with medial cartilage lesions (coefficient 2.50, 95% confidence interval 0.61-4.40, p < 0.01). Disability for ADL of the patients was associated with BMLs in the medial side of the knee joint (0.82, 0.21-1.02, p = 0.04). BMLs in the medial side of the knee joint were associated with disability for ADL of patients with early stage medial knee OA.

Preoperative timed single leg standing time is associated with the postoperative activity of daily living in aged disabled patients with end-stage knee osteoarthritis at six-months after undergoing total knee arthroplasty.

OBJECTIVES: The aim of the present study was to investigate the effect size (ES) of total knee arthroplasty (TKA) for the symptoms and lower limb function and identify preoperative factor(s) associated with the post-operative activity of daily living (ADL) in aged patients with end-stage knee OA undergoing TKA. METHODS: Fifty-nine aged patients with end-stage knee OA (mean age: 74.6 years) were enrolled in this study. The symptoms and lower limb function of the patients were evaluated using the Japanese Knee Osteoarthritis Measure (JKOM), the timed up and go (TUG) test and timed single-legged stance test with eyes open (TSLS) before and after six months from the operation. RESULTS: While the ES of TKA for the improvement of pain was 2.83, the ES of TKA for the improvement of ADL, TUG and TSLS were 1.30, 0.59, and 0.49, respectively. While the post-operative ADL score was not associated with the preoperative ADL or pain scores, it was associated with the preoperative TUG and TSLS scores. A multiple regression analysis revealed that the one preoperative factor associated with the postoperative ADL was the TSLS. CONCLUSION: The preoperative TSLS is associated with the postoperative ADL in aged disabled patients with end-stage knee OA.

The MRI-detected osteophyte score is a predictor for undergoing joint replacement in patients with end-stage knee osteoarthritis.

OBJECTIVES: The aim of this prospective cohort study was to examine whether MRI-detected osteoarthritis (OA)-structural changes at baseline could predict knee OA patients who would undergo total knee arthroplasty (TKA). METHODS: In total, 128 end-stage medial-type knee OA patients were enrolled and followed up for 6 months. MRI using the whole-organ MRI scoring (WORMS) method, radiographic findings, visual analog scale (VAS) for pain and a patient-oriented outcome measure, and the Japanese Knee Osteoarthritis Measure (JKOM) were recorded at baseline. The area under the curve (AUC) was estimated to determine the discriminative value of the prediction models. RESULTS: While 74 patients (57.8%) did not undergo TKA, the remaining 54 patients (42.2%) underwent TKA during this period. The AUCs of the receiver operating characteristic (ROC) curve for the activities of daily living (ADL) score evaluated by the JKOM ADL score [0.70 (95% CI: 0.60-0.79)] and osteophyte score [0.72 (0.64-0.81)] were 0.70 or greater. The JKOM ADL score (17/40) and the osteophyte score (30/98) showed relative risks (RR) of 2.61 (1.32-5.15) and 3.01 (1.39-6.52) for undergoing TKA, respectively. CONCLUSION: The osteophyte score detected by MRI, in addition to ADL score, was found to be an important factor in determining whether the patient should undergo TKA.

Disability for daily living is a predictor for joint replacement in patients with end-stage knee osteoarthritis.

The objective indicators which reflect the past results of end-stage knee osteoarthritis (OA) patients who have already received total knee arthroplasty (TKA) could be helpful for physicians to discuss with patients who are considering TKA. The aim of this prospective cohort study was to examine whether we could predict the knee OA patients who would receive TKA in advance based on baseline data, and to set cut-off points for receiving TKA. The two-hundred and forty end-stage medial-type knee OA patients were enrolled and followed up for 6 months while performing therapeutic exercises. Radiographic findings, visual analog scale for pain and a patient-oriented outcome measure, the Japanese Knee Osteoarthritis Measure (JKOM), were recorded at baseline. Relative risks (RRs) using the area under the curve (AUC) for a receiver operating characteristic (ROC) curve were calculated to evaluate several scores for receiving TKA. While 119 patients (55.3 %) did not undergo TKA, the remaining 96 patients (44.7 %) underwent TKA during this period. The AUCs of the ROC curve for the JKOM total score [0.71 (95 % CI 0.64-0.79)] were higher than those for radiographic parameters. Among the JKOM subcategories, JKOM category III, which indicates the condition in daily life, showed the highest AUC of 0.72 (0.65-0.80). The JKOM total score (65/100) and JKOM category III score (17/40) showed RRs of 2.20 (1.33-3.63) and 1.95 (1.18-3.22) for receiving TKA, respectively. The presence of disability in daily living was found to be an important factor determining whether the patient should undergo TKA.

Reference intervals of serum hyaluronic acid corresponding to the radiographic severity of knee osteoarthritis in women.

BACKGROUND: While serum levels of hyarulonic acid (sHA) is known to be useful for a burden of disease biomarker in knee OA, it is far from practical. The reference intervals must be established for biomarkers to be useful for clinical interpretation. The aim of this study was to establish the reference intervals of sHA corresponding to the radiographic severity of knee OA for elucidating whether sHA can be useful as a burden of disease marker for individual patient with knee OA. METHODS: 372 women with Kellgren & Lawrence grade (K/L) 1 through 4 painful knee OA were enrolled in this study. The patients included 54 with K/L 1, 96 with K/L 2, 97 with K/L 3, and 118 with K/L 4. Serum samples were obtained from all subjects on the day that radiographs taken. A HA binding protein based latex agglutination assay that employed an ELISA format was used to measure sHA. Age and BMI adjusted one way ANOVA was used to set the reference intervals of sHA. RESULTS: The reference intervals for sHA corresponding to the patients with K/L 4 (49.6 - 66.5 ng/ml) was established without any overlap against to those with K/L 1, 2 and 3, while those with K/L 1, 2 and 3 showed considerable overlap. CONCLUSIONS: These results indicate that sHA can be available as a burden of disease marker for the individuals with severe knee OA (K/L 4), while it is not for those with primary to moderate knee OA (K/L 1-3).

Correlations between both the expression levels of inflammatory mediators and growth factor in medial perimeniscal synovial tissue and the severity of medial knee osteoarthritis.

An enhanced expression of the inflammatory mediators in the perimeniscal synovium in knee osteoarthritis (OA) has been suggested to contribute to progressive cartilage degeneration. However, whether the expression levels of these molecules correlated with the severity of OA still remained unclear. Medial perimeniscal synovial samples were obtained from 23 patients with Kellgren-Lawrence (K/L) grades 2 to 4 of medial knee OA. Immunohistochemical analysis of the synovium revealed that the MMP-1, COX-2 and IL-1ß expression of the patients with K/L 4 to be significantly reduced in comparison to those with either K/L 2 or 3, while the TGF-ß expression showed the opposite. The synovial expression of MMP-1 and IL-1ß showed a significant negative correlation with the severity of OA, while that of TGF-ß again showed the opposite. In conclusion, although synovial inflammation remained active, the MMP-1, COX-2 and IL-1ß expression in synovium decreased depending upon the severity of OA, while the TGF-ß expression increased.

Perlecan is required for the chondrogenic differentiation of synovial mesenchymal cells through regulation of Sox9 gene expression.

We previously reported that perlecan, a heparan-sulfate proteoglycan (Hspg2), expressed in the synovium at the cartilage-synovial junction, is required for osteophyte formation in knee osteoarthritis. To examine the mechanism underlying this process, we examined the role of perlecan in the proliferation and differentiation of synovial mesenchymal cells (SMCs), using a recently established mouse synovial cell culture method. Primary SMCs isolated from Hspg2-/- -Tg (Hspg2-/- ;Col2a1-Hspg2Tg/- ) mice, in which the perlecan-knockout was rescued from perinatal lethality, lack perlecan. The chondrogenic-, osteogenic-, and adipogenic-potentials were examined in the Hspg2-/- -Tg SMCs compared to the control SMCs prepared from wild-type Hspg2+/+ -Tg (Hspg2+/+ ;Col2a1-Hspg2Tg/- ) littermates. In a culture condition permitting proliferation, both control and Hspg2-/- -Tg SMCs showed similar rates of proliferation and expression of cell surface markers. However, in micromass cultures, the cartilage matrix production and Sox9 and Col2a1 mRNA levels were significantly reduced in Hspg2-/- -Tg SMCs, compared with control SMCs. The reduced level of Sox9 mRNA was restored by the supplementation with exogenous perlecan protein. There was no difference in osteogenic differentiation between the control and Hspg2-/- -Tg SMCs, as measured by the levels of Runx2 and Col1a1 mRNA. The adipogenic induction and PPARγ mRNA levels were significantly reduced in Hspg2-/- -Tg SMCs compared to control SMCs. The reduction of PPARγ mRNA levels in Hspg2-/- -Tg SMCs was restored by supplementation of perlecan. Perlecan is required for the chondrogenic and adipogenic differentiation from SMCs via its regulation of the Sox9 and PPARγ gene expression, but not for osteogenic differentiation via Runx2. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:837-846, 2017.

Association of medial meniscal extrusion with medial tibial osteophyte distance detected by T2 mapping MRI in patients with early-stage knee osteoarthritis.

BACKGROUND: Medial meniscal extrusion (MME) is associated with progression of medial knee osteoarthritis (OA), but no or little information is available for relationships between MME and osteophytes, which are found in cartilage and bone parts. Because of the limitation in detectability of the cartilage part of osteophytes by radiography or conventional magnetic resonance imaging (MRI), the rate of development and size of osteophytes appear to have been underestimated. Because T2 mapping MRI may enable us to evaluate the cartilage part of osteophytes, we aimed to examine the association between MME and OA-related changes, including osteophytes, by using conventional and T2 mapping MRI. METHODS: Patients with early-stage knee OA (n = 50) were examined. MRI-detected OA-related changes, in addition to MME, were evaluated according to the Whole-Organ Magnetic Resonance Imaging Score. T2 values of the medial meniscus and osteophytes were measured on T2 mapping images. Osteophytes surgically removed from patients with end-stage knee OA were histologically analyzed and compared with findings derived by radiography and MRI. RESULTS: Medial side osteophytes were detected by T2 mapping MRI in 98% of patients with early-stage knee OA, although the detection rate was 48% by conventional MRI and 40% by radiography. Among the OA-related changes, medial tibial osteophyte distance was most closely associated with MME, as determined by multiple logistic regression analysis, in the patients with early-stage knee OA (ß = 0.711, p < 0.001). T2 values of the medial meniscus were directly correlated with MME in patients with early-stage knee OA, who showed ≥ 3 mm of MME (r = 0.58, p = 0.003). The accuracy of osteophyte evaluation by T2 mapping MRI was confirmed by histological analysis of the osteophytes removed from patients with end-stage knee OA. CONCLUSIONS: Our study demonstrates that medial tibial osteophyte evaluated by T2 mapping MRI is frequently observed in the patients with early-stage knee OA, showing close association with MME, and that MME is positively correlated with the meniscal degeneration.

Synovial perlecan is required for osteophyte formation in knee osteoarthritis.

The osteophyte associated with osteoarthritis (OA) is a bony outgrowth formed at the margins of the affected joint through endochondral ossification-like processes. However, the mechanism of osteophyte formation and its pathogenesis are unclear. Perlecan (Hspg2), a heparan sulfate proteoglycan, is expressed in many extracellular tissues and plays critical roles in skeletal development and diseases. The aim of the present study is to identify the role of synovial perlecan in osteophyte formation using perinatal lethality rescued perlecan-knockout mice (Hspg2(-/-)-Tg) wherein perlecan expression is lacking in the synovial and other tissues, except for cartilage. We analyzed the development of osteophytes in joints of Hspg2(-/-)-Tg mice in two different animal models: the surgical OA model, in which the medial collateral ligament was transected and the medial meniscus was resected, and the TGF-ß-induced osteophyte formation model. In the surgical OA model, the osteophyte size and maturation were significantly reduced in the OA joints of Hspg2(-/-)-Tg mice compared with control mice, while OA developed on the medial side of the knee joints with no differences in the cartilage degradation score or synovitis score between control and Hspg2(-/-)-Tg mice. The reduced osteophyte formation in Hspg2(-/-)-Tg mice was associated with reduced cell proliferation and chondrogenesis. In the TGF-ß model, the osteophyte size and maturation were also significantly reduced in Hspg2(-/-)-Tg mice compared with control mice. Our findings suggest that synovial perlecan plays an important role in osteophyte development in OA, and they provide insights that may facilitate the development of OA therapy.

Isolation and characterization of multipotential mesenchymal cells from the mouse synovium.

The human synovium contains mesenchymal stem cells (MSCs), which are multipotential non-hematopoietic progenitor cells that can differentiate into a variety of mesenchymal lineages and they may therefore be a candidate cell source for tissue repair. However, the molecular mechanisms by which this can occur are still largely unknown. Mouse primary cell culture enables us to investigate the molecular mechanisms underlying various phenomena because it allows for relatively easy gene manipulation, which is indispensable for the molecular analysis. However, mouse synovial mesenchymal cells (SMCs) have not been established, although rabbit, cow, and rat SMCs are available, in addition to human MSCs. The aim of this study was to establish methods to harvest the synovium and to isolate and culture primary SMCs from mice. As the mouse SMCs were not able to be harvested and isolated using the same protocol for human, rat and rabbit SMCs, the protocol for humans was modified for SMCs from the Balb/c mouse knee joint. The mouse SMCs obtained showed superior proliferative potential, growth kinetics and colony formation compared to cells derived from muscle and bone marrow. They expressed PDGFRá and Sca-1 detected by flow cytometry, and showed an osteogenic, adipogenic and chondrogenic potential similar or superior to the cells derived from muscle and bone marrow by demonstrating in vitro osteogenesis, adipogenesis and chondrogenesis. In conclusion, we established a primary mouse synovial cell culture method. The cells derived from the mouse synovium demonstrated both the ability to proliferate and multipotentiality similar or superior to the cells derived from muscle and bone marrow.

Relationships between biomarkers of cartilage, bone, synovial metabolism and knee pain provide insights into the origins of pain in early knee osteoarthritis.

INTRODUCTION: We tested the hypothesis that there exist relationships between the onset of early stage radiographically defined knee osteoarthritis (OA), pain and changes in biomarkers of joint metabolism. METHODS: Using Kellgren-Lawrence (K/L) grading early radiographic knee OA (K/L 2) was detected in 16 of 46 patients. These grades (K/L 1 is no OA and K/L 2 is early OA) were divided into two groups according to the presence or absence of persistent knee pain. Sera (s) and urines (u) were analysed with biomarkers for cartilage collagen cleavage (sC2C and uCTX-II) and synthesis (sCPII), bone resorption (uNTx) and synovitis (hyaluronic acid: sHA). RESULTS: sCPII decreased and sC2C/sCPII, uCTX-II/sCPII and sHA increased with onset of OA (K/L 2 versus K/L 1) irrespective of joint pain. In contrast, sC2C and uCTX-II remained unchanged in early OA patients. Of the patients with K/L grades 1 and 2 sC2C, sCPII, sHA, uNTX and uCTX-II were all significantly increased in patients with knee pain independent of grade. Among the K/L grade 2 subjects, only uCTX-II and uCTX-II/sCPII were increased in those with knee pain. In grade 1 patients both sC2C and sCPII were increased in those with knee pain. No such grade specific changes were seen for the other biomarkers including sHA. CONCLUSIONS: These results suggest that changes in cartilage matrix turnover detected by molecular biomarkers may reflect early changes in cartilage structure that account directly or indirectly for knee pain. Also K/L grade 1 patients with knee pain exhibit biomarker features of early OA.

Distinct mechanosensitive Ca2+ influx mechanisms in human primary synovial fibroblasts.

Synovial cells are exposed to continually changing dynamic forces and are implicated in the maintenance of joint homeostasis. However, the mechanisms of synovial cell responses to mechanical stress are unclear. In this study, we investigated the difference between the mechanosensitive channels of human primary synovial fibroblasts (SFBs) and human primary dermal fibroblasts (DFBs) in response to mechanical stretch by uniaxial cyclic stretching and mechanical cell membrane deformation in vitro. Cyclic stretching induced orientation of SFBs and DFBs perpendicularly to the stretching direction. Furthermore, uniaxial stretching increased intracellular Ca(2+) levels in both cell types. The perpendicular orientation of DFBs was blocked by gadolinium (III) chloride (Gd(3+), a mechanosensitive Ca(2+) channel blocker) or ruthenium red (RR, a nonselective Ca(2+) channel blocker). However, Gd(3+) did not block the stretch-induced perpendicular orientation in SFBs, while RR inhibited this orientation. Similarly, Ca(2+) influx in DFBs induced by uniaxial stretching and membrane deformation was inhibited by Gd(3+), RR, and GsMTx-4 (another mechanosensitive Ca(2+) channel blocker), while only RR inhibited Ca(2+) influx in SFBs. Our results suggest that SFBs respond to mechanical stretch through mechanosensitive channels that are distinct from those of DFBs.

Correlation between synovitis detected on enhanced-magnetic resonance imaging and a histological analysis with a patient-oriented outcome measure for Japanese patients with end-stage knee osteoarthritis receiving joint replacement surgery.

Osteoarthritis (OA) is a disease that primarily results in the degeneration and destruction of the articular cartilage. However, synovitis that occurs secondarily by this primary phenomenon is crucial for both the structural and symptomatic progression of the disease. The Japanese Knee Osteoarthritis Measure (JKOM) was created as an outcome measure for Japanese patients with knee OA. This study was conducted to determine whether synovitis in knee OA correlates with the current disability of patients with knee OA who required total knee arthroplasty (TKA). Thirty-four Japanese patients with end-stage knee OA who required TKA were included in this study. The visual analog scale (VAS, 0-100) for pain and the JKOM score, as well as the Western Ontario and McMaster Universities Arthritis Index (WOMAC), were examined before the operation. Synovial samples were taken at the time of the operation. A histological analysis and gadolinium-enhanced magnetic resonance imaging (Gd-MRI) were conducted to evaluate synovitis. Correlations between the synovitis score evaluated by histological analysis and Gd-MRI with either the pain VAS score or the JKOM score were examined using Spearman's rank correlation coefficient. Neither the synovitis scores evaluated by the histological analysis nor those by a Gd-MRI correlated with the pain VAS score (n = 34, r = 0.25, p = 0.18 and r = 0.08, p = 0.75, respectively) and WOMAC (n = 14, r = 0.35, p = 0.22 and r = 0.45, p = 0.16, respectively) of the patients. However, they significantly correlated with the JKOM score of the patients (n = 34, r = 0.55, p = 0.001 and r = 0.71, p = 0.001, respectively). The severity of synovitis in OA was closely correlated with the current functional impairment and disability of the patients receiving TKA with end-stage knee OA.