Pioglitazone,a peroxisome proliferator–activated receptor γ agonist,reduces the progression of experimental osteoarthritis in guinea pigs

Objective

To evaluate the in vivo therapeutic effect of pioglitazone, a peroxisome proliferator–activated receptor γ (PPARγ) agonist, on the development of lesions in a guinea pig model of osteoarthritis (OA), and to determine the influence of pioglitazone on the synthesis of matrix metalloproteinase 13 (MMP‐13) and interleukin‐1β (IL‐1β) in articular cartilage.

Methods

The OA model was created by partial medial meniscectomy of the right knee joint. The guinea pigs were divided into 4 treatment groups: unoperated animals that received no treatment (normal), operated animals (OA guinea pigs) that received placebo, OA guinea pigs that received oral pioglitazone at 2 mg/kg/day, and OA guinea pigs that received oral pioglitazone at 20 mg/kg/day. The animals began receiving medication 1 day after surgery and were killed 4 weeks later. Macroscopic and histologic analyses were performed on the cartilage. The levels of MMP‐13 and IL‐1β in OA cartilage chondrocytes were evaluated by immunohistochemistry.

Results

OA guinea pigs treated with the highest dosages of pioglitazone showed a significant decrease, compared with the OA placebo group, in the surface area (size) and grade (depth) of cartilage macroscopic lesions on the tibial plateaus. The histologic severity of cartilage lesions was also reduced. A significantly higher percentage of chondrocytes in the middle and deep layers stained positive for MMP‐13 and IL‐1β in cartilage from placebo‐treated OA guinea pigs compared with normal controls. Guinea pigs treated with the highest dosage of pioglitazone demonstrated a significant reduction in the levels of both MMP‐13 and IL‐1β in OA cartilage.

Conclusion

This is the first in vivo study demonstrating that a PPARγ agonist, pioglitazone, could reduce the severity of experimental OA. This effect was associated with a reduction in the levels of MMP‐13 and IL‐1β, which are known to play an important role in the pathophysiology of OA lesions.

     

Effects of chronic growth hormone and insulin‐like growth factor 1 deficiency on osteoarthritis severity in rat knee joints

Objective

To determine the effects of chronic deficiency of growth hormone (GH) and insulin‐like growth factor 1 (IGF‐1) on osteoarthritis (OA) severity.

Methods

Thirty‐five rats were divided into 4 treatment groups at 4 weeks of age: 1 control group (normal GH/IGF‐1 levels [heterozygous]) and 3 groups of dwarves with a genetic mutation that results in GH deficiency. The first dwarf group received GH for 64 weeks (GH replete) and the second received GH until 14 weeks of age, followed by saline for 50 weeks (adult‐onset GH/IGF‐1 deficiency [AO‐GHD]). The third dwarf group received saline injections only (lifetime GH deficient [GHD]). Sections of the medial knee joint compartment were graded and measured histologically; data were summarized using factor analysis, and treatment effects were assessed using analysis of variance and adjusting for body weight.

Results

Terminal IGF‐1 levels and body weights were significantly affected by treatment (P = 0.002 and P < 0.001, respectively). Factor analysis yielded a total of 5 factors, the first 3 of which were not significantly affected by treatment. Factor 4 (weighted by medial tibial plateau articular cartilage width and area) was significantly affected by treatment (P < 0.012), with larger values in the AO‐GHD group than in the GHD group (P < 0.05). Factor 5 (weighted primarily by articular cartilage structure and loss of toluidine blue staining scores) also was significantly affected by treatment (P < 0.001), and was significantly lower (less severe lesions) in the GH replete group than in all other treatment groups (P < 0.05). Despite the presence of cartilage lesions, osteophytes and subchondral sclerosis were not observed in GH/IGF‐1–deficient animals.

Conclusion

These results indicate that chronic GH/IGF‐1 deficiency causes an increased severity of articular cartilage lesions of OA without the bony lesions normally seen in this disease.

     

Immunohistochemical analysis of hip arthritis in ankylosing spondylitis: Evaluation of the bone–cartilage interface and subchondral bone marrow

Objective

Previous histopathologic and magnetic resonance imaging studies suggest that the subchondral bone marrow might be the primary site of inflammation in patients with ankylosing spondylitis (AS) and that this might be reflected by inflammation found in hip joints. The aim of this study was to conduct an immunohistologic assessment of the bone–cartilage interface and subchondral bone marrow in AS patients with hip arthritis.

Methods

We collected femoral heads from patients with AS, osteoarthritis (OA), and rheumatoid arthritis (RA) who were undergoing hip replacement. The subchondral bone marrow and bone–cartilage interface were assessed immunohistochemically by evaluating infiltrating T cells, microvessel density, and osteoclasts. Areas of the femoral head surface with and without cartilage were assessed separately.

Results

At sites with surface cartilage, we found subchondral infiltration of CD3+ T cell aggregates at significantly higher numbers in AS patients as compared with OA patients, but not RA patients. At sites of complete cartilage destruction, the frequency of CD3+ T cell aggregates was significantly reduced as compared with sites with cartilage on the surface in AS patients, but not in RA patients. Similar differences were found for CD4+ and CD8+ T cells. Only at sites with surface cartilage, but not those without, angiogenesis and osteoclastic foci in the subchondral bone marrow in AS patients were significantly increased as compared with RA patients and with OA patients.

Conclusion

These findings suggest that the subchondral bone marrow and bone–cartilage interface are primary sites of inflammation in AS and that cartilage might be necessary for the induction of inflammation.

     

Matrix metalloproteinases and aggrecanases cleave aggrecan in different zones of normal cartilage but colocalize in the development of osteoarthritic lesions in STR/ort mice

Objective

To map aggrecan cleavage by matrix metalloproteinases (MMPs) and aggrecanases in normal murine tibial articular cartilage (CBA strain) and in the development of spontaneous osteoarthritis (OA) in the STR/ort mouse and to assess the influence of sex hormone status on these conditions in gonadectomized STR/ort mice.

Methods

The distributions of neoepitopes of aggrecan generated by MMP (VDIPEN) and aggrecanase (NITEGE) cleavage were investigated by immunohistochemistry.

Results

VDIPEN neoepitope was detected mainly in the pericellular matrix of deep‐zone chondrocytes in normal tibial cartilage from STR/ort and CBA mice. In early OA, VDIPEN immunostaining also localized to the pericellular matrix of chondrocytes at the site of the lesion. With increasing severity of OA lesions, VDIPEN immunostaining was also detected in the interterritorial matrix, close to the site of the lesion. In contrast, NITEGE mapped most strongly to the pericellular matrix of upper‐zone chondrocytes in normal tibial cartilage. As with VDIPEN, NITEGE was strongly expressed in the pericellular matrix at the site of early OA lesions. With advancing OA, NITEGE colocalized with VDIPEN in both the pericellular and interterritorial matrices of chondrocytes adjacent to OA lesions and in those of the deep zones. Hormone status did not appear to influence the development of OA or the distribution of aggrecan neoepitopes in STR/ort mice.

Conclusion

MMP‐ and aggrecanase‐generated neoepitopes map predominantly to different regions in normal murine tibial cartilage. However, both groups of enzymes generate increased amounts of neoepitopes in pericellular and interterritorial matrix adjacent to histopathologic lesions of OA. Aggrecan degradation and the development of OA appear to be independent of sex hormone status in this model.

     

Trabecular morphometry by fractal signature analysis is a novel marker of osteoarthritis progression

Objective

To evaluate the effectiveness of using subchondral bone texture observed on a radiograph taken at baseline to predict progression of knee osteoarthritis (OA) over a 3‐year period.

Methods

A total of 138 participants in the Prediction of Osteoarthritis Progression study were evaluated at baseline and after 3 years. Fractal signature analysis (FSA) of the medial subchondral tibial plateau was performed on fixed flexion radiographs of 248 nonreplaced knees, using a commercially available software tool. OA progression was defined as a change in joint space narrowing (JSN) or osteophyte formation of 1 grade according to a standardized knee atlas. Statistical analysis of fractal signatures was performed using a new model based on correlating the overall shape of a fractal dimension curve with radius.

Results

Fractal signature of the medial tibial plateau at baseline was predictive of medial knee JSN progression (area under the curve [AUC] 0.75, of a receiver operating characteristic curve) but was not predictive of osteophyte formation or progression of JSN in the lateral compartment. Traditional covariates (age, sex, body mass index, knee pain), general bone mineral content, and joint space width at baseline were no more effective than random variables for predicting OA progression (AUC 0.52–0.58). The predictive model with maximum effectiveness combined fractal signature at baseline, knee alignment, traditional covariates, and bone mineral content (AUC 0.79).

Conclusion

We identified a prognostic marker of OA that is readily extracted from a plain radiograph using FSA. Although the method needs to be validated in a second cohort, our results indicate that the global shape approach to analyzing these data is a potentially efficient means of identifying individuals at risk of knee OA progression.

     

ERK‐1/2 and p38 in the regulation of hypertrophic changes of normal articular cartilage chondrocytes induced by osteoarthritic subchondral osteoblasts

Objective

Previous studies have shown the influence of subchondral bone osteoblasts (SBOs) on phenotypical changes of articular cartilage chondrocytes (ACCs) during the development of osteoarthritis (OA). The molecular mechanisms involved during this process remain elusive, in particular, the signal transduction pathways. The aim of this study was to investigate the in vitro effects of OA SBOs on the phenotypical changes in normal ACCs and to unveil the potential involvement of MAPK signaling pathways during this process.

Methods

Normal and arthritic cartilage and bone samples were collected for isolation of ACCs and SBOs. Direct and indirect coculture models were applied to study chondrocyte hypertrophy under the influence of OA SBOs. MAPKs in the regulation of the cell–cell interactions were monitored by phosphorylated antibodies and relevant inhibitors.

Results

OA SBOs led to increased hypertrophic gene expression and matrix calcification in ACCs by means of both direct and indirect cell–cell interactions. In this study, we demonstrated for the first time that OA SBOs suppressed p38 phosphorylation and induced ERK‐1/2 signal phosphorylation in cocultured ACCs. The ERK‐1/2 pathway inhibitor PD98059 significantly attenuated the hypertrophic changes induced by conditioned medium from OA SBOs, and the p38 inhibitor SB203580 resulted in the up‐regulation of hypertrophic genes in ACCs.

Conclusion

The findings of this study suggest that the pathologic interaction of OA SBOs and ACCs is mediated via the activation of ERK‐1/2 phosphorylation and deactivation of p38 phosphorylation, resulting in hypertrophic differentiation of ACCs.

     

The peroxisome proliferator–activated receptor γ agonist pioglitazone reduces the development of cartilage lesions in an experimental dog model of osteoarthritis: In vivo protective effects mediated through the inhibition of key signaling and catabolic pathways

Objective

Emerging evidence indicates that peroxisome proliferator–activated receptor γ (PPARγ) may have protective effects in osteoarthritis (OA). The aim of this study was to evaluate the in vivo effect of a PPARγ agonist, pioglitazone, on the development of lesions in a canine model of OA, and to explore the influence of pioglitazone on the major signaling and metabolic pathways involved in OA pathophysiologic changes.

Methods

OA was surgically induced in dogs by sectioning of the anterior cruciate ligament. The dogs were then randomly divided into 3 treatment groups in which they were administered either placebo, 15 mg/day pioglitazone, or 30 mg/day pioglitazone orally for 8 weeks. Following treatment, the severity of cartilage lesions was scored. Cartilage specimens were processed for histologic and immunohistochemical evaluations; specific antibodies were used to study the levels of matrix metalloproteinase 1 (MMP‐1), ADAMTS‐5, and inducible nitric oxide synthase (iNOS), as well as phosphorylated MAPKs ERK‐1/2, p38, JNK, and NF‐κB p65.

Results

Pioglitazone reduced the development of cartilage lesions in a dose‐dependent manner, with the highest dosage producing a statistically significant change (P < 0.05). This decrease in lesions correlated with lower cartilage histologic scores. In addition, pioglitazone significantly reduced the synthesis of the key OA mediators MMP‐1, ADAMTS‐5, and iNOS and, at the same time, inhibited the activation of the signaling pathways for MAPKs ERK‐1/2, p38, and NF‐κB.

Conclusion

These results indicate the efficacy of pioglitazone in reducing cartilage lesions in vivo. The results also provide new and interesting insights into a therapeutic intervention for OA in which PPARγ activation can inhibit major signaling pathways of inflammation and reduce the synthesis of cartilage catabolic factors responsible for articular cartilage degradation.

     

Assessing bone loss on radiographs of the knee in osteoarthritis: A cross‐sectional study

Objective

The only established system to grade subchondral bone attrition in knee osteoarthritis (OA) has low interobserver reliability. In this study, our aim was to convert this system into a reliable tool for the assessment of subchondral bone loss in knee OA.

Methods

Templates that were designed to outline the normal contours of the knee were overlaid onto conventional radiographs of a random sample of 100 knees of OA patients who were awaiting total knee replacement (TKR). Seventy‐five films from individuals with chronic knee pain who were not awaiting TKR and 75 films from asymptomatic control subjects were also assessed. Bone loss was graded from 0 (no attrition) to 3 (severe attrition of >10 mm); other established radiologic features were also graded. Spearman's rho was used to determine the correlation of attrition scores with other features, and logistic regression was used to explore whether definite bone attrition was associated with night pain.

Results

The inter‐ and intraobserver reliability values were high for attrition scores and for the presence of definite attrition (score ≥2). Bone attrition was evident in 62% of films from patients awaiting TKR, in 9% of films from individuals with chronic knee pain who were not awaiting TKR, and in 1% of films from controls. In all groups, the correlation between attrition and other features was weak to moderate. There was a nonsignificant association between definite bone attrition and night pain.

Conclusion

Bone attrition is an additional dimension of knee OA that can be measured reliably. Definite attrition may be associated with night pain.

     

Increased friction coefficient and superficial zone protein expression in patients with advanced osteoarthritis

Objective

To quantify the concentration of superficial zone protein (SZP) in the articular cartilage and synovial fluid of patients with advanced osteoarthritis (OA) and to further correlate the SZP content with the friction coefficient, OA severity, and levels of proinflammatory cytokines.

Methods

Samples of articular cartilage and synovial fluid were obtained from patients undergoing elective total knee replacement surgery. Additional normal samples were obtained from donated body program and tissue bank sources. Regional SZP expression in cartilage obtained from the femoral condyles was quantified by enzyme‐linked immunosorbent assay (ELISA) and visualized by immunohistochemistry. Friction coefficient measurements of cartilage plugs slid in the boundary lubrication system were obtained. OA severity was graded using histochemical analyses. The concentrations of SZP and proinflammatory cytokines in synovial fluid were determined by ELISA.

Results

A pattern of SZP localization in knee cartilage was identified, with load‐bearing regions exhibiting high SZP expression. SZP expression patterns were correlated with friction coefficient and OA severity; however, SZP expression was observed in all samples at the articular surface, regardless of OA severity. SZP expression and aspirate volume of synovial fluid were higher in OA patients than in normal controls. Expression of cytokines was elevated in the synovial fluid of some patients.

Conclusion

Our findings indicate a mechanochemical coupling in which physical forces regulate OA severity and joint lubrication. The findings of this study also suggest that SZP may be ineffective in reducing joint friction in the boundary lubrication mode at an advanced stage of OA, where other mechanisms may dominate the observed tribological behavior.

     

Quality of well‐being in older people with osteoarthritis

Objective

To examine the sensitivity of the Quality of Well‐Being Scale (QWB) as a measure of health‐related quality of life (HRQOL) in people with osteoarthritis (OA).

Methods

The QWB was administered, along with the Arthritis Impact Measurement Scale (AIMS) and other health measures. Health care utilization data were also obtained.

Results

People with OA had a mean QWB score of 0.643. The QWB scores were significantly correlated with total AIMS scores, self‐rated health status, health care costs, depression scores, and most AIMS subscales. In addition, changes in QWB scores after 1 year were significantly correlated with changes in total AIMS scores and some AIMS subscales.

Conclusion

The QWB appears to be a useful and sensitive generic, utility‐based measure of HRQOL in people with OA.

     

In vivo bone‐specific EphB4 overexpression in mice protects both subchondral bone and cartilage during osteoarthritis

Objective

In vitro activation of the receptor EphB4 positively affects human osteoarthritis (OA) articular cell metabolism. However, the specific in vivo role of this ephrin receptor in OA remains unknown. We investigated in mice the in vivo effect of bone‐specific EphB4 overexpression on OA pathophysiology.

Methods

Morphometric, morphologic, and radiologic evaluations were performed on postnatal day 5 (P5) mice and on 10‐week‐old mice. Knee OA was induced surgically by destabilization of the medial meniscus (DMM) in 10‐week‐old male EphB4 homozygous transgenic (EphB4‐Tg) and wild‐type (WT) mice. Medial compartment evaluations of cartilage were performed using histology and immunohistochemistry, and evaluations of subchondral bone using histomorphometry, osteoclast staining, and micro–computed tomography.

Results

There was no obvious phenotype difference in skeletal development between EphB4‐Tg mice and WT mice at P5 or at 10 weeks. At 8 and 12 weeks post‐DMM, the EphB4‐Tg mice demonstrated significantly less cartilage alteration in the medial tibial plateau and the femoral condyle than did the WT mice. This was associated with a significant reduction of aggrecan and type II collagen degradation products, type X collagen, and collagen fibril disorganization in the operated EphB4‐Tg mice. The medial tibial subchondral bone demonstrated a significant reduction in sclerosis, bone volume, trabecular thickness, and number of tartrate‐resistant acid phosphatase–positive osteoclasts at both times assessed post‐DMM in the EphB4‐Tg mice than in the WT mice.

Conclusion

This is the first in vivo evidence that bone‐specific EphB4 overexpression exerts a protective effect on OA joint structural changes. The findings of this study stress the in vivo importance of subchondral bone biology in cartilage integrity.

     

Extreme obesity due to impaired leptin signaling in mice does not cause knee osteoarthritis

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.

     

A randomized controlled trial to evaluate the slow‐acting symptom‐modifying effects of colchicine in osteoarthritis of the knee: A preliminary report

Objective

To determine if colchicine added to nimesulide may have a beneficial effect on osteoarthritis (OA) of the knee.

Methods

Colchicine 0.5 mg twice daily or placebo was added to nimesulide (a nonsteroidal antiinflammatory drug) in 36 patients with OA of the knee in a randomized, double‐blind, placebo‐controlled trial over a 5‐month period.

Results

The 30% improvement rate at 20 weeks was higher in the colchicine group than in the control group receiving placebo, as measured by total Western Ontario and McMaster University Osteoarthritis scores (57.9% versus 23.5%) and visual analog scale for index knee pain (52.6% versus 17.6%) (primary measures of response). The significance persisted on combined analysis by Mantel‐Haenszel test (P = 0.062). Comparison of means also showed significant improvement in the colchicine group versus the control group in a multivariate analysis performed using T² test (P = 0.0115).

Conclusion

Among patients with OA of the knee, the group receiving colchicine plus nimesulide exhibited significantly greater symptomatic benefit at 20 weeks than did the control group receiving nimesulide plus placebo.

     

Alteration of sensory neurons and spinal response to an experimental osteoarthritis pain model

Objective

To verify the biologic links between progressive cellular and structural alterations within knee joint components and development of symptomatic chronic pain that are characteristic of osteoarthritis (OA), and to investigate the molecular basis of alterations in nociceptive pathways caused by OA‐induced pain.

Methods

An animal model of knee joint OA pain was generated by intraarticular injection of mono‐iodoacetate (MIA) in Sprague‐Dawley rats, and symptomatic pain behavior tests were performed. Relationships between development of OA with accompanying pain responses and gradual alterations in cellular and structural knee joint components (i.e., cartilage, synovium, meniscus, subchondral bone) were examined by histologic and immunohistologic analysis, microscopic examination, and microfocal computed tomography. Progressive changes in the dynamic interrelationships between peripheral knee joint tissue and central components of nociceptive pathways caused by OA‐induced pain were examined by investigating cytokine production and expression in sensory neurons of the dorsal root ganglion and spinal cord.

Results

We observed that structural changes in components of the peripheral knee joint correlate with alterations in the central compartments (dorsal root ganglia and the spinal cord) and symptomatic pain assessed by behavioral hyperalgesia. Our comparative gene expression studies revealed that the pain pathways in MIA‐induced knee OA may overlap, at least in part, with neuropathic pain mechanisms. Similar results were also observed upon destabilization of the knee joint in the anterior cruciate ligament transection and destabilization of the medial meniscus models of OA.

Conclusion

Our results indicate that MIA‐induced joint degeneration in rats generates an animal model that is suitable for mechanistic and pharmacologic studies on nociceptive pain pathways caused by OA, and provide key in vivo evidence that OA pain is caused by central sensitization through communication between peripheral OA nociceptors and the central sensory system. Furthermore, our data suggest a mechanistic overlap between OA‐induced pain and neuropathic pain.

     

Use of alternative therapies by older adults with osteoarthritis

Objective

To examine the rates of use and expenditures on alternative therapies by adults with osteoarthritis (OA).

Methods

Adults with OA recruited from the community to participate in a randomized clinical trial recorded alternative and traditional health care use on postcard diaries. General and arthritis‐specific quality of life was assessed by questionnaires.

Results

More than 47% of participants reported using at least one type of alternative care during the 20‐week intervention period. Among alternative care consumers, the most commonly used treatments were massage therapy (57%), chiropractic services (20.7%), and nonprescribed alternative medications (17.2%). Four percent of subjects reported using only alternative care during the study period. Expenditures for alternative therapy averaged $1,127 per year, compared with $1,148 for traditional therapies.

Conclusion

Use of and expenditures for alternative care were high among this cohort of older adults with OA. Clinicians may want to inquire about use of these therapies before recommending treatments for this condition.

     

Tidal irrigation as treatment for knee osteoarthritis: A sham‐controlled,randomized, double‐blinded evaluation

Objective

To evaluate the effectiveness of tidal irrigation (TI) in comparison with a well‐matched sham irrigation (SI) procedure as a treatment for knee osteoarthritis (OA).

Methods

One hundred eighty subjects with knee OA were randomized to receive TI or SI, with clinical followup over the ensuing 12 months. The primary outcomes of interest were change in pain and function, as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Subjects and the nurse assessor were blinded, and success of blinding was assessed.

Results

Although the study groups were otherwise comparable, the baseline WOMAC pain and physical functioning scores were higher (worse) in the SI group. After adjustment for baseline, there were no differences between the effects of SI and TI. Blinding was successful, with ∼90% of SI and TI subjects stating that they had received the TI procedure.

Conclusion

Most, if not all, of the effect of TI appears to be attributable to a “placebo response.”

     

Denuded subchondral bone and knee pain in persons with knee osteoarthritis

Objective

It is unclear how articular cartilage loss contributes to pain in patients with knee osteoarthritis (OA). Full‐thickness cartilage defects expose the subchondral bone plate. The relationship between denuded bone and pain has not been examined. The aim of this study was to investigate whether the percent of denuded bone is associated with moderate‐to‐severe knee pain or frequent knee pain and longitudinally with frequent knee pain 2 years after the baseline evaluation.

Methods

We studied 182 persons with knee OA (305 knees). Applying specialized magnetic resonance imaging techniques, manual segmentation was used to compute cartilage‐covered and denuded bone areas for each surface. Moderate‐to‐severe knee pain was defined as a score of ≥40 mm on a knee‐specific 100‐mm visual analog scale, and frequent knee pain was defined as pain on most days during the past month. Logistic regression and generalized estimating equations were used in analyses, adjusting for age, sex, body mass index, and bone marrow lesions.

Results

Cross‐sectional analyses revealed that moderate‐to‐severe knee pain was associated with percent denuded bone in the medial compartment (adjusted odds ratio [OR] 3.90, 95% confidence interval [95% CI] 1.33–11.47), in the medial and patellar surfaces together, and in the lateral and patellar surfaces. Frequent knee pain was associated with percent denuded bone in the patellar surface (adjusted OR 3.11, 95% CI 1.24–7.81), in the medial and patellar surfaces, and in the lateral and patellar surfaces. Longitudinal analyses (in 168 knees without frequent knee pain at baseline) revealed that percent denuded bone in the medial and patellar surfaces was associated with frequent incident knee pain (adjusted OR 4.19, 95% CI 1.56–11.22).

Conclusion

These results support a relationship between subchondral bone plate exposure and prevalent and incident knee pain in patients with knee OA.

     

Proliferative remodeling of the spatial organization of human superficial chondrocytes distant from focal early osteoarthritis

Objective

Human superficial chondrocytes show distinct spatial organizations, and they commonly aggregate near osteoarthritic (OA) fissures. The aim of this study was to determine whether remodeling or destruction of the spatial chondrocyte organization might occur at a distance from focal (early) lesions in patients with OA.

Methods

Samples of intact cartilage (condyles, patellofemoral groove, and proximal tibia) lying distant from focal lesions of OA in grade 2 joints were compared with location‐matched nondegenerative (grade 0–1) cartilage samples. Chondrocyte nuclei were stained with propidium iodide, examined by fluorescence microscopy, and the findings were recorded in a top‐down view. Chondrocyte arrangements were tested for randomness or significant grouping via point pattern analyses (Clark and Evans Aggregation Index) and were correlated with the OA grade and the surface cell densities.

Results

In grade 2 cartilage samples, superficial chondrocytes were situated in horizontal patterns, such as strings, clusters, pairs, and singles, comparable to the patterns in nondegenerative cartilage. In intact cartilage samples from grade 2 joints, the spatial organization included a novel pattern, consisting of chondrocytes that were aligned in 2 parallel lines, building double strings. These double strings correlated significantly with an increased number of chondrocytes per group and an increased corresponding superficial zone cell density. They were observed in all grade 2 condyles and some grade 2 tibiae, but never in grade 0–1 cartilage.

Conclusion

This study is the first to identify a distinct spatial reorganization of human superficial chondrocytes in response to distant early OA lesions, suggesting that proliferation had occurred distant from focal early OA lesions. This spatial reorganization may serve to recruit metabolically active units as an attempt to repair focal damage.

     

Discordance between pain and radiographic severity in knee osteoarthritis: Findings from quantitative sensory testing of central sensitization

Objective

Radiographic measures of the pathologic changes of knee osteoarthritis (OA) have shown modest associations with clinical pain. We sought to evaluate possible differences in quantitative sensory testing (QST) results and psychosocial distress profiles between knee OA patients with discordant versus congruent clinical pain reports relative to radiographic severity measures.

Methods

A total of 113 participants (66.7% women; mean ± SD age 61.05 ± 8.93 years) with knee OA participated in the study. Radiographic evidence of joint pathology was graded according to the Kellgren/Lawrence scale. Central sensitization was indexed through quantitative sensory testing, including heat and pressure–pain thresholds, tonic suprathreshold pain (cold pressor test), and repeated phasic suprathreshold mechanical and thermal pain. Subgroups were constructed by dichotomizing clinical knee pain scores (median split) and knee OA grade scores (grades 1–2 versus 3–4), resulting in 4 groups: low pain/low knee OA grade (n = 24), high pain/high knee OA grade (n = 32), low pain/high knee OA grade (n = 27), and high pain/low knee OA grade (n = 30).

Results

Multivariate analyses revealed significantly heightened pain sensitivity in the high pain/low knee OA grade group, while the low pain/high knee OA grade group was less pain‐sensitive. Group differences remained significant after adjusting for differences on psychosocial measures, as well as age, sex, and race.

Conclusion

The results suggest that central sensitization in knee OA is especially apparent among patients with reports of high levels of clinical pain in the absence of moderate‐to‐severe radiographic evidence of pathologic changes of knee OA.