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Biomedical subjects

R W Moskowitz

Publications and source records attributed to R W Moskowitz.

At least 19 recordsLinked to original sources

An analgesic model for assessment of acute pain response in osteoarthritis of the knee.

BACKGROUND: Osteoarthritis (OA) is frequently treated only during periods of flare, in which rapid onset of analgesia is the outcome target. OBJECTIVE: To assess an acute pain model of knee OA in flare. METHODS: In a multicenter, randomized, double-blind, controlled study, 530 patients aged >or=50 years received valdecoxib 10 mg qd (n=212), rofecoxib 2 5 mg qd (n=208), or placebo (n=110). Pain intensity (PI) was measured on a visual analog scale (VAS) at baseline after a 10-min walk. Patients took their first dose of study medication, rested for 20 min, then measured their PI VAS at 0.5, 1, 1.5, 2, 3, 4, 5, and 6h, each time following a 10-min walk. RESULTS: PI VAS differences (PID) were significantly greater vs placebo both with valdecoxib and rofecoxib (P<0.05) beginning as early as 3h (intent-to-treat population). The percentage of patients with analgesia onset from 4h was significantly higher with both valdecoxib (55%) and rofecoxib (56%) relative to placebo (40%). Median time to first onset of analgesic was shorter with both valdecoxib and rofecoxib compared with placebo (P=0.104 vs valdecoxib; P=0.036 vs rofecoxib). CONCLUSIONS: This acute pain model of knee OA flare detected significant pain relief with agents known to relieve pain in OA and placebo within hours after the first treatment dose, allowing assessment of pain relief within hours rather than days or weeks when evaluating analgesic efficacy in OA. This model is undergoing further study to determine optimal walk times, distances, and rates to maximize its sensitivity.

Acute Disease↗

Musculoskeletal findings in obese subjects before and after weight loss following bariatric surgery.

OBJECTIVE: To determine the point prevalence of painful musculoskeletal (MSK) conditions in obese subjects before and after weight loss following bariatric surgery. DESIGN: Longitudinal, interventional, unblended. SUBJECTS: Forty-eight obese subjects (47 women, one man, mean age 44+/-9 years; mean body mass index (BMI) 51+/-8 kg/m(2)) recruited from an academic medical center bariatric surgery program. MEASUREMENTS: Comorbid medical conditions; MSK findings; BMI; Western Ontario McMaster Osteoarthritis Index (WOMAC) for pain, stiffness and function; and SF-36 for quality of life. METHODS: Consecutive subjects were recruited from the University Hospitals of Cleveland Bariatric Surgery Program. Musculoskeletal signs and symptoms and non-MSK comorbid conditions were documented at baseline and at follow-up. SUBJECTS completed the SF-36 and the WOMAC questionnaires. Analyses were carried out for each MSK site, fibromyalgia syndrome (FMS) and for the cumulative effect on the spine, upper and lower extremities. The impact of change in comorbid medical conditions, BMI, physical and mental health domains of the SF-36 on the WOMAC pain subscale score was evaluated. SF-36 outcomes were compared to normal published controls. RESULTS: Forty-eight subjects were available for baseline and a follow-up assessment 6-12 months after gastric bypass surgery. They lost an average of 41+/-15 kg and the mean BMI decreased from 51+/-8 to 36+/-7 kg/m(2). Baseline comorbid medical conditions were present in 96% before surgery and 23% after weight loss. There was an increased prevalence of painful MSK conditions at baseline compared to general population frequencies. Musculoskeletal complaints had been present in 100% of obese subjects before, and 23% after weight loss. The greatest improvements occurred in the cervical and lumbar spine, the foot and in FMS (decreased by 90, 83, 83 and 92%, respectively). Seventy-nine percent had upper extremity MSK conditions before and 40% after weight loss. Before surgery, 100% had lower extremity MSK conditions and only 37% did after weight loss. The WOMAC subscale and composite scores all improved significantly, as did the SF-36((R)). Change in BMI was the main factor impacting the WOMAC pain score. CONCLUSION: There was a higher frequency of multiple MSK complaints, including non-weight-bearing sites compared to historical controls, before surgery, which decreased significantly at most sites following weight loss and physical activity. These benefits may improve further, as weight loss may continue for up to 24 months. The benefits seen with weight loss indicate that prevention and treatment of obesity can improve MSK health and function.

Adult↗

Hip joint replacement surgery for idiopathic osteoarthritis aggregates in families.

In order to determine whether there is a genetic component to hip or knee joint failure due to idiopathic osteoarthritis (OA), we invited patients (probands) undergoing hip or knee arthroplasty for management of idiopathic OA to provide detailed family histories regarding the prevalence of idiopathic OA requiring joint replacement in their siblings. We also invited their spouses to provide detailed family histories about their siblings to serve as a control group. In the probands, we confirmed the diagnosis of idiopathic OA using American College of Rheumatology criteria. The cohorts included the siblings of 635 probands undergoing total hip replacement, the siblings of 486 probands undergoing total knee replacement, and the siblings of 787 spouses. We compared the prevalence of arthroplasty for idiopathic OA among the siblings of the probands with that among the siblings of the spouses, and we used logistic regression to identify independent risk factors for hip and knee arthroplasty in the siblings. Familial aggregation for hip arthroplasty, but not for knee arthroplasty, was observed after controlling for age and sex, suggesting a genetic contribution to end-stage hip OA but not to end-stage knee OA. We conclude that attempts to identify genes that predispose to idiopathic OA resulting in joint failure are more likely to be successful in patients with hip OA than in those with knee OA.

Aged↗

A newly described hereditary cartilage debonding syndrome.

OBJECTIVE: We describe a hereditary chondropathy characterized by extreme cartilage friability and cartilage-bone debonding, which has not previously been described in the literature. We also describe initial studies into the molecular basis of this disorder. METHODS: Affected family members had multiple shoulder, hip, and knee arthropathies, beginning in the pre-teen years and continuing into adulthood. Various diagnoses had been suggested, including spondyloepiphyseal dysplasia, multiple epiphyseal dysplasia, Legg-Calvé-Perthes disease, and Osgood-Schlatter disease. The affected proband father, his 3 affected children, and unaffected family members provided blood samples, which were examined for single-nucleotide polymorphisms (SNPs) in the chromosome 2 region that included the Frizzled-related protein gene, a soluble Wnt protein signaling antagonist that influences bone and cartilage development. RESULTS: All affected individuals showed clear similarities, including effusions, large loose bodies, and bubbling and delamination of the cartilage with exposure of subchondral bone. All affected individuals exhibited radiographic changes in the hip, showing femoral head flattening and secondary degenerative arthritis, accompanied by abnormalities in the physical properties of the cartilage that were evident upon arthroscopic examination. Two SNPs were identified in subjects with the hereditary cartilage debonding syndrome. Examination of the siblings and parents of the proband demonstrated, however, that both SNPs were present in the unaffected mother and in 2 of 4 unaffected siblings of the proband. CONCLUSION: The clinical findings reported here represent a newly defined clinical syndrome characterized by marked cartilage friability and osteochondral debonding. Because the SNPs are present in the general population, and because unaffected members of this family carry the SNPs, these polymorphisms alone are insufficient to result in the observed phenotype.

Adolescent↗

Expression profile of protein tyrosine kinase genes in human osteoarthritis chondrocytes.

OBJECTIVE: To determine the expression profile of protein kinase (PK) and protein tyrosine kinase (PTK) genes in human primary osteoarthritis (OA) chondrocytes and to compare it with that of immortalized human chondrocytes T/C 28a4 with a view to learning whether T/C 28a4 cells can be used for elucidating signal transduction pathways in human chondrocytes. DESIGN: We used the Atlas Human cDNA Array and a method based on PCR with degenerate primers to analyse the expression profile of protein kinase genes in primary human OA chondrocytes and compared it with that of immortalized human chondrocyte cell line T/C 28a4 using RT-PCR and Western blotting. RESULTS: A total of 21 PTK genes were identified and several of these have never been shown to be expressed in human OA chondrocytes. Comparative expression analysis of some selected kinase genes showed that the mRNA expression pattern of many protein kinase genes in OA chondrocytes was identical to that of T/C 28a4 cells. However, there were differences in the level of protein expression of selected protein kinases in these cells. For example, mRNA expression of the novel kinase HCK was detected in OA chondrocytes and in the cell lines analysed but by Western blotting HCK protein was not detected in OA chondrocytes. In these studies, we also identified a novel mutant form of the discoidin domain receptor 2 (DDR2) transcript from chondrocyte-like cell line HTB-94. CONCLUSIONS: Our results provide novel information about protein kinase gene expression in OA chondrocytes and indicate that the transformed chondrocyte cell line T/C 28a4 may be suitable for elucidating signal transduction pathways in chondrocytes and to investigate how they regulate chondrocyte function in inflammatory and degenerative joint diseases.

Blotting, Western↗

Involvement of caspase-3 in epigallocatechin-3-gallate-mediated apoptosis of human chondrosarcoma cells.

Green tea polyphenol-(-)epigallocatechin-3-gallate (EGCG)-is a potent chemopreventive agent in many test systems and has been shown to inhibit tumor promotion and induce apoptosis. In this study we describe a novel observation that EGCG displayed strong inhibitory effects on the proliferation and viability of HTB-94 human chondrosarcoma cells in a dose-dependent manner and induced apoptosis. Investigation of the mechanism of EGCG-induced apoptosis revealed that treatment with EGCG resulted in DNA fragmentation, induction of caspase-3/CPP32 activity, and cleavage of the death substrate poly(ADP-ribose)polymerase (PARP). Pretreatment of cells with a synthetic pan-caspase inhibitor (Z-VAD-FMK) and a caspase-3-specific inhibitor (DEVD-CHO) prevented EGCG-induced PARP cleavage. The induction of apoptosis by EGCG via activation of caspase-3/CPP32-like proteases may provide a mechanistic explanation for its antitumor effects.

Antineoplastic Agents↗

Tumour necrosis factor alpha enhances the expression of hydroxyl lyase, cytoplasmic antiproteinase-2 and a dual specificity kinase TTK in human chondrocyte-like cells.

Tumour necrosis factor alpha (TNF-alpha) is a cytokine with pleiotropic effects on cells ranging from proliferation to apoptosis. These biological effects of TNF-alpha are believed to be elicited by the induction or enhancement of the expression of TNF-alpha responsive genes in the target cells. TNF-alpha is pro-inflammatory and a principal mediator in the pathogenesis of arthritis. The activation of an inflammatory cascade by TNF-alpha in arthritis results in the degradation of cartilage, joint destruction and loss of function. Because TNF-alpha is an important mediator in the pathogenesis of arthritis, the present study addresses the identification of novel TNF-alpha responsive genes in HTB-94 cell line which is of human origin and maintains a chondrocytic phenotype. The three identified cDNAs were previously not known to be induced or upregulated by TNF-alpha in chondrocytes or cells of chondrocytic lineage. One of the identified cDNAs had sequence similarity to human hydroxyl lyase mRNA (PLOD), an enzyme involved in collagen biosynthesis and its metabolism; the second cDNA had sequence similarity to the human cytoplasmic anti-proteinase-2 mRNA (CAP-2), a member of a group of proteins shown to be associated with protecting cells from TNF-alpha-induced apoptosis; and the third cDNA had sequence similarity to a dual specificity kinase, TTK, which is associated with cell proliferation. Relative gene expression level analysis by PCR and by Northern blotting revealed that treatment with TNF-alpha enhanced the expression of PLOD, CAP2 and TTK transcripts which confirmed the results obtained with display gels. Furthermore, TTK mRNA expression was also induced in human articular chondrocytes treated with TNF-alpha but not in untreated chondrocytes. Our results suggest that these genes may play a role in chondrocytic responses to TNF-alpha-mediated stimuli affecting the cartilage homeostasis.

Base Sequence↗

Hyaluronic acid supplementation.

As evidenced by publication of a new set of guidelines for the treatment of osteoarthritis (OA) by the American College of Rheumatology after only 5 years, modalities available for the management of OA have undergone significant changes. New therapeutic approaches include the use of cyclo-oxygenase-2 inhibitors, and intra-articular hyaluronans (HA). HA, found in a number of body tissues, is altered in the presence of osteoarthritis with decreased molecular weight and concentration resulting in impaired viscoelasticity. Hyaluronan preparations have been shown to decrease pain and increase function in patients with osteoarthritis of the knee. Mechanisms of therapeutic effect include restoration of more normal synovial fluid with improved viscoelasticity, effects on cartilage biosynthesis and degradation, anti-inflammatory effects, and direct analgesic effects. Studies in animal models, and preliminary studies in humans suggest that hyaluronans may have a structure-modifying effect in OA. Hyaluronans represent a substantive addition to the therapeutic armamentarium in osteoarthritis.

Adjuvants, Immunologic↗

Role of collagen hydrolysate in bone and joint disease.

OBJECTIVES: To review the current status of collagen hydrolysate in the treatment of osteoarthritis and osteoporosis. METHODS: Review of past and current literature relative to collagen hydrolysate metabolism, and assessment of clinical investigations of therapeutic trials in osteoarthritis and osteoporosis. RESULTS: Hydrolyzed gelatin products have long been used in pharmaceuticals and foods; these products are generally recognized as safe food products by regulatory agencies. Pharmaceutical-grade collagen hydrolysate (PCH) is obtained by hydrolysis of pharmaceutical gelatin. Clinical studies suggest that the ingestion of 10 g PCH daily reduces pain in patients with osteoarthritis of the knee or hip; blood concentration of hydroxyproline is increased. Clinical use is associated with minimal adverse effects, mainly gastrointestinal, characterized by fullness or unpleasant taste. In a multicenter, randomized, doubleblind, placebo-controlled trial performed in clinics in the United States, United Kingdom, and Germany, results showed no statistically significant differences for the total study group (all sites) for differences of mean pain score for pain. There was, however, a significant treatment advantage of PCH over placebo in German sites. In addition, increased efficacy for PCH as compared to placebo was observed in the overall study population amongst patients with more severe symptomatology at study onset. Preferential accumulation of 14C-labeled gelatin hydrolysate in cartilage as compared with administration of 14C-labeled proline has been reported. This preferential uptake by cartilage suggests that PCH may have a salutary effect on cartilage metabolism. Given the important role for collagen in bone structure, the effect of PCH on bone metabolism in osteoporotic persons has been evaluated. Studies of the effects of calcitonin with and without a collagen hydrolysate-rich diet suggested that calcitonin plus PCH had a greater effect in inhibiting bone collagen breakdown than calcitonin alone, as characterized by a fall in levels of urinary pyridinoline cross-links. PCH appeared to have an additive effect relative to use of calcitonin alone. CONCLUSIONS: Collagen hydrolysate is of interest as a therapeutic agent of potential utility in the treatment of osteoarthritis and osteoporosis. Its high level of safety makes it attractive as an agent for long-term use in these chronic disorders.

Amino Acids↗

Changes in serum cartilage marker levels indicate altered cartilage metabolism in families with the osteoarthritis-related type II collagen gene COL2A1 mutation.

OBJECTIVE: The Arg5l9-Cys mutation in type II collagen results in severe, precocious familial osteoarthritis (OA) in 100% of carriers within the first 3 decades of life. The carrier population provided a well-defined patient population for the study of serum markers of familial OA with respect to pathogenesis, diagnosis, and prognosis. METHODS: Serum was obtained from 31 mutation-positive individuals and 16 mutation-negative individuals. OA severity was determined by clinical and radiologic assessments. Levels of serum cartilage oligomeric matrix protein (COMP), keratan sulfate (KS) epitope, the 846 epitope of aggrecan, and the C propeptide of type II collagen (CPII) were measured and were correlated with the radiologic findings. RESULTS: COMP and KS levels, both of which have been suggested to be indicative of disturbed cartilage turnover, were significantly elevated in mutation-positive individuals and in the individuals with OA regardless of mutation status. There was no statistically significant difference between mutation-positive, mutation-negative, OA-positive, and OA-negative individuals with respect to serum concentrations of epitope 846 or CPII, both of which are putative markers of cartilage repair. CONCLUSION: Study of the macromolecular constituents of cartilage released into serum in subjects with familial OA revealed altered metabolism in OA, as demonstrated by elevated COMP and KS levels. Other constituents, the 846 epitope and CPII, were not altered, indicating dissociation of cartilage anabolism and breakdown. Future sequential studies will provide an opportunity to define biochemical changes as familial OA develops and to monitor therapeutic responses.

Adult↗

Nutraceuticals as therapeutic agents in osteoarthritis. The role of glucosamine, chondroitin sulfate, and collagen hydrolysate.

There are a sufficient number of short-term studies with these agents suggesting efficacy equal to that seen in the symptomatic treatment of OA using NSAIDs. Two recent meta-analyses by McAlindon and colleagues and Towheed et al reviewed clinical trials of glucosamine and chondroitin in the treatment of osteoarthritis. The study by McAlindon and co-workers included all double-blind placebo-controlled trials of greater than 4 weeks' duration, testing oral or parenteral glucosamine or chondroitin for treatment of hip or knee osteoarthritis. Thirteen trials (six with glucosamine, seven with chondroitin) met eligibility criteria. The authors used global pain score or the Lequesne index in the index joint as the primary outcome measure and considered the trial positive if improvement in the treatment group was equal to or greater than 25% compared with the placebo group, and was significant (P < or = .05). All 13 studies reviewed were classified as positive, demonstrating large effects, compared with placebo (39.5% [S.D. 21.9] for glucosamine, 40.2% [S.D. 6.4] for chondroitin). The authors concluded that clinical trials of these two agents showed substantial benefit in the treatment of osteoarthritis but provided insufficient information about study design and conduct to allow definitive evaluation. Towheed and colleagues reviewed nine randomized, controlled trials of glucosamine sulfate in osteoarthritis. In seven of the randomized controlled trials, in which they compared glucosamine with placebo, glucosamine was always superior. In two randomized controlled trials comparing glucosamine to ibuprofen, glucosamine was superior in one and equivalent in one. Methodologic problems, including lack of standardized case definition of osteoarthritis and lack of standardized outcome assessment led the authors to conclude that further studies are needed to determine if route of administration is important and whether the therapeutic effect is site specific. A meta-analysis of chondroitin sulfate trials has also been published. Of the 12 published trials, 4 randomized double-blind placebo or NSAID-controlled trials with 227 patients on chondroitin sulfate were entered into the analysis. All four studies showed chondroitin sulfate to be superior to placebo, with respect to Lequesne index, visual analog scale for pain and medication consumption. Significant changes (P < or = .05) were seen in those treated from day 60 to the study endpoints (150 to 180 days). Pooled data demonstrated at least 50% improvement in the study variables in the chondroitin treated group. Discrepancies in some of the study findings reported in the literature may relate to the composition of the nutritional supplements used. Studies in the United States have revealed that a number of preparations claiming to contain certain doses of glucosamine or chondroitin sulfate have significantly less (or none) of the dosages described. Accordingly, it is essential that studies performed with these agents use preparations that are carefully defined in manufacture. The amounts generally administered are glucosamine, 1500 mg, and chondroitin sulfate, 1200 mg, daily. Although glucosamine has been described as effective when used alone, it is probably reasonable to use the combination pending further studies. The average cost is approximately $30 to $45 per month. In the interim, what should physicians tell their patients when they ask whether these agents are effective, or whether they should or should not take them? The authors emphasize that these agents are not FDA-evaluated or recommended for the treatment of OA. They are available as health food supplements, and the number of studies of toxicity, particularly with respect to long-term evaluations, is limited. The pros and cons of these agents and the published data are described so that patients can make a reasonably informed decision as to whether they wish to proceed with use of these agents in therapy. (ABSTRACT TRUNCATED)

Animals↗

Glucose regulation of the IGF response system in chondrocytes: induction of an IGF-I-resistant state.

Nonresponsiveness to the growth-stimulatory actions of insulin-like growth factor (IGF)-I in chondrocytes has been reported in a number of disease states associated with impaired glucose metabolism. Primary rabbit chondrocytes were investigated for changes in their IGF response system [type-I IGF receptor and IGF-binding protein (IGFBP) expression] and in their ability to mount a synthetic response to IGF-I [as 35S-labeled proteoglycan ([35S]PG) production] in media containing varying ambient glucose concentrations. Whereas basal [35S]PG synthetic rate was unaffected by glucose concentration, synthetic responsiveness to IGF-I was lost in media containing <5 mmol/l glucose or in media containing a "diabetic" glucose concentration (25 mmol/l). IGFBP expression, as measured by Northern analysis of mRNA levels and Western ligand blotting of secreted protein levels, was not significantly altered in the different glucose media, nor were there any differences in the cell surface localization of IGFBPs as assessed by affinity cross-linking with 125I-labeled IGF-I, suggesting that IGFBPs do not induce the IGF-I resistance. The nonresponsiveness to IGF-I in reduced glucose occurred with 25-50% reductions in steady-state levels of IGF type-I receptor mRNA and protein. A significant correlation between IGF receptor mRNA level and synthetic response to IGF-I was observed between 0 and 10 mmol/l glucose concentrations, suggesting that the loss of responsiveness in reduced glucose is manifested at the level of transcription and/or receptor mRNA stability. In contrast, nonresponsiveness to IGF-I in chondrocytes in diabetic glucose concentrations occurred without changes in receptor mRNA and protein levels, suggesting that IGF-I resistance was due to post-ligand-binding receptor defects. It is proposed that IGF-I resistance in chondrocytes subjected to inappropriate glucose levels may constitute an important pathogenic mechanism in degenerative cartilage disorders.

Animals↗