Biomedical subjects

J C Fernandes

Publications and source records attributed to J C Fernandes.

At least 19 recordsLinked to original sources

PubMed2006

Evidence for two distinct pathways in TNFalpha-induced membrane and soluble forms of ICAM-1 in human osteoblast-like cells isolated from osteoarthritic patients.

OBJECTIVE: The present study aimed to investigate the modulation of membrane-bound intercellular adhesion molecule-1 (mICAM-1) and soluble ICAM-1 (sICAM-1) expression by tumor necrosis factor-alpha (TNFalpha) in human osteoarthritic (OA) osteoblasts. METHODS: Cultured human primary osteoblasts were stimulated with increasing concentrations of human recombinant TNFalpha. Expression of mICAM-1 and sICAM-1 was evaluated by immunocytochemistry, enzyme-linked immunosorbent assay and semi-quantitative reverse transcriptase-polymerase chain reaction. In addition, we investigated the molecular mechanisms underlying ICAM-1 induction by TNFalpha, focusing on the activation of the mitogen-activated protein kinases (MAPKs) and nuclear factor-kappaB (NF-kappaB) pathways. RESULTS: Our data showed that TNFalpha dose-dependently increased mICAM-1 and sICAM-1 expression at the protein and mRNA levels in OA osteoblasts. The inhibitor of de novo mRNA synthesis, actinomycin D, suppressed TNFalpha-induced mICAM-1 and sICAM-1 expression. Upon examination of the signaling components, we found that TNFalpha was a potent activator of p38, p44/42, p54/46 MAPK, and IkappaBalpha (IkappaBalpha). The chemical inhibitors of p38, p44/42 MAPK, and NF-kappaB blocked TNFalpha-induced mICAM-1 expression but not that of sICAM-1. Transfection experiments revealed that p38 MAPK or IkappaB kinase alpha (IKKalpha) overexpression enhanced TNFalpha-induced mICAM-1 production. Furthermore, osteoblasts treatment with a chemical inhibitor of metalloproteinase-9 (MMP-9) activity, a proteolytic enzyme involved in ICAM-1 cleavage, evoked a significant 25% decrease of TNFalpha-induced sICAM-1 release. CONCLUSION: Taken together, these findings illustrate the central role played by TNFalpha in the regulation of ICAM-1. We suggest that TNFalpha differentially regulates sICAM-1 and mICAM-1 expression and that sICAM-1 release involves, in part, the proteolytic cleavage of mICAM-1 by MMP-9. The capacity of the MMP-9 inhibitor to prevent sICAM-1 production may be useful for the development of novel therapeutic approaches relevant to OA.

Dactinomycin↗

PubMed2006

Cyclosporin A treatment in severe childhood psoriasis.

Though used occasionally, systemic therapies in severe childhood psoriasis have not been systematically investigated. Cyclosporin A (CysA) is effective in adults with severe psoriasis but there are no extensive data regarding the efficacy and safety of its use in childhood psoriasis. In this paper, we describe six children aged between 11 months and 13 years (average: 7.6 years) treated with CysA microemulsion formulation for severe psoriasis, who had been unresponsive to other treatments. The CysA dose ranged from 2 to 4 mg/kg/day, for periods varying from 8 to 105 weeks (mean: 54 weeks). Dose tapering was gradual after lesion improvement and adjusted according to clinical response. Adjuvant therapy with topical steroids, vitamin D3 ointments, coal tar preparations or anthralin was used in all children. Acitretin was used in three patients for short periods. The children were regularly monitored for serum renal and liver function and blood pressure. Improvement of skin lesions was achieved after between 4 and 30 (mean: 12) weeks of treatment, with complete remission in three children. Relapse of lesions occurred in the other children during CysA reduction, but they responded to a dose increase. The treatment was found to be well tolerated and with no significant side-effects. CysA can be used in carefully selected and monitored patients and may represent an alternative tool for severe episodes of psoriasis in children, when other therapies are unsuccessful.

Adolescent↗

PubMed2005

Subchondral and trabecular bone metabolism regulation in canine experimental knee osteoarthritis.

OBJECTIVE: To determine trabecular and subchondral bone metabolic changes in experimental canine osteoarthritis (OA). METHODS: OA was induced in 19 dogs by transection of the anterior cruciate ligament (ACL) of the right knee through a stab wound. Dogs were sacrificed at 8 (n=7) and 12 weeks (n=12) after surgery. Non-operated normal dogs (n=6) were used as controls. After sacrifice, samples were obtained from the weight-bearing area of medial tibial plateaus. Explants and cell cultures were prepared from subchondral and trabecular bone. Osteocalcin (Oc), cellular alkaline phosphatase (ALPase), urokinase plasminogen-activator (uPA), prostaglandin E2 (PGE2), metalloproteinase (MMP) and nitric oxide (NO) were measured using standard procedures. RESULTS: ALPase production was significantly increased only at week 12 in subchondral and trabecular bone, while an increase in Oc was noted at week 8. uPA and MMP activity were increased significantly at week 12 in subchondral bone, while PGE2 levels were significantly higher in subchondral and trabecular bone at week 12 compared to normal. A decrease in NO production appeared late at week 12 in trabecular bone, whereas NO levels from subchondral bone were significantly increased compared to normal at week 8. DISCUSSION: Intense bone remodeling takes place in both subchondral and trabecular bone in the knee following ACL transection. This process seems to occur around week 12, although Oc and NO appeared to be involved earlier at 8 weeks. These results suggest that not only subchondral but also trabecular bone metabolism is altered in this OA model.

Alkaline Phosphatase↗

PubMed2004

[Who cares how doctors and patients relate?].

The relationship between doctors and their patients is part of everyday life for thousands of professionals. In order to avoid an idealistic or merely emotional approach to this question, it is necessary to investigate how it is related to medical science and to the overall relationship between medicine and society. Indeed, far from being aleatory, the doctor-patient relationship as it has been practiced can be understood as a tool for maintaining the power of both the medical establishment and the state over society. To change this practice, the author proposes two different approaches to specific fields of medical practice: the hospital and non-hospital fields. In the field outside hospitals, the humanization of medical practice depends basically on broadened training for professionals in order to prepare them to deal with this work's inherent demands, where a physiopathological approach is often insufficient. Inside hospitals, a more humanistic relationship depends more directly on the action of a multiprofessional health team.

English Abstract↗

PubMed2004

[Conceptual aspects of educational practices for HIV/AIDS prevention].

The importance and complexity of educational work related to HIV prevention demand a continuing discussion of its contents. Regarding the ideologic features, it must be assumed that, with the AIDS epidemic, medical science reaches a dimension of the life relatively preserved from its previous hegemonic position: sexual behavior. In this field, a coercive attitude on the part of health professionals may lead to negative reactions. To avoid this, individual and community participation and self-responsibility are central tools for the improvement of the efficacy of education practices. The author proposes three components that educational planners should consider: information and its effects on knowledge, attitudes, and perception related to HIV infection; response facilitation; and support for individual and collective reflection.

English Abstract↗

PubMed2004

Treatment with licofelone prevents abnormal subchondral bone cell metabolism in experimental dog osteoarthritis.

OBJECTIVES: To determine if treatment with licofelone, a combined 5-lipoxygenase and cyclo-oxygenase inhibitor, in vivo in experimental dog osteoarthritis can modify bone cell metabolism in long term in vitro subchondral osteoblast cell cultures (Ob). METHODS: Group 1 received sectioning of the anterior cruciate ligament (ACL) of the right knee with no active treatment (placebo group). Groups 2 and 3 received sectioning of the ACL of the right knee, and were given licofelone (2.5 or 5.0 mg/kg daily by mouth, respectively) for eight weeks beginning the day after surgery. Primary Ob were prepared from the subchondral bone plate. Levels of phenotypic markers (alkaline phosphatase activity, osteocalcin release), and urokinase plasminogen activator (uPA) and insulin-like growth factor-1 (IGF-I) levels, were evaluated in each group. Lastly, prostaglandin E(2) (PGE(2)) and leucotriene B(4) levels were evaluated. RESULTS: No significant differences in alkaline phosphatase activity or osteocalcin release from Ob between the three groups, under either basal or 1,25(OH)(2)D(3) induction were seen. In contrast, treatment with licofelone reduced uPA and IGF-I levels in Ob. PGE(2) levels, which were still raised in the placebo group, were decreased sharply by licofelone. A relationship was found between licofelone treatment and either the reduction in the size of lesions on tibial plateaus or the levels of uPA, IGF-I, or PGE(2). CONCLUSIONS: Licofelone treatment prevents and/or delays the abnormal metabolism of subchondral osteoblasts in this model. Licofelone reduced PGE(2) levels after long term Ob, suggesting that the reduction in uPA and IGF-I levels is linked, at least in part, to this reduction.

Acetates↗

PubMed2002

Peroxisome proliferator-activated receptor gamma activators inhibit MMP-1 production in human synovial fibroblasts likely by reducing the binding of the activator protein 1.

OBJECTIVE: To investigate the expression and activity of PPARgamma in human synovial fibroblasts and the effects of PPARgamma agonists on the expression of MMP-1. The molecular mechanisms by which PPARgamma agonists modulate MMP-1 expression were also examined. METHODS: PPARgamma expression and activity were measured using reverse-transcription polymerase chain reaction (RT-PCR) and transient transfection assays. Human synovial fibroblasts were cultured with IL-1beta in the absence or presence of PPARgamma activators, and the expression and production of MMP-1 were evaluated by Northern blot and ELISA, respectively. The effect of 15d-PGJ(2) on MMP-1 promoter activation was analysed in transient transfection experiments, while electrophoretic mobility shift assays were performed to study the binding activity of the transcription factor AP-1. RESULTS: PPARgamma was expressed and transcriptionally functional in human synovial fibroblasts. PPARgamma activators (15d-PGJ(2) and BRL 49653) inhibited IL-1beta-induced MMP-1 synthesis in a dose-dependent manner. Similarly, both activators inhibited IL-1-induced MMP-1 mRNA expression. Activation of the human MMP-1 promoter was also attenuated by 15d-PGJ(2), indicating that the inhibitory effect of 15d-PGJ(2) occurs at the transcriptional level. Interestingly, 15d-PGJ(2) reduced both basal and IL-1beta-induced AP-1 binding activity. CONCLUSIONS: These data indicate that PPARgamma agonists inhibit MMP-1 gene expression by transcriptional mechanisms, and suggest that they may be useful in reducing joint tissue destruction.

Aged↗

PubMed2002

Modulation of IL-1beta, IL-6, TNF-alpha and PGE(2) by pharmacological agents in explants of membranes from failed total hip replacement.

Introduction and goal Proinflammatory cytokines and prostaglandin E(2) (PGE(2)) play an important role in the pathophysiology of osteolysis and implant loosening. The aim of this study was to evaluate the role of pharmacological agents in the inhibition of Interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) and PGE(2) in explants of interface membranes from failed total hip replacements (fTHR). Material and methods Membranes from fTHR were retrieved (N=20) and explants were incubated for 72h in the absence or presence of tenidap at three different concentrations (5, 20 or 50 microg/ml) or diclofenac (125 microg/l). IL-1beta, IL-6, TNF-alpha, and PGE(2) levels were measured in the culture medium using ELISA Capture or EIA kits. Statistical analysis was done using the Mann-Whitney U-test. Results A statistically significant inhibition in IL-1beta synthesis was found at tenidap concentrations of 20 microg/ml (71.3%, P< 0.05) and 50 microg/ml (79.3%,P< 0.02). Tenidap reduced IL-6 levels by 90.4% at 20 microg/ml (P< 0.005) and 96.0% (P< 0.05) at 50 microg/ml. Tenidap also reduced the synthesis of TNF-alpha by 66.9% (P< 0.05) and 77.4% at concentrations of 20 microg/ml and 50 microg/ml. Tenidap had a marked suppressive effect of over 90% (P< 0.0001) on PGE(2) synthesis in all three concentrations. Diclofenac (125 microg/l) decreased PGE(2) production by 95% (P< 0.0001), but had no significant effect in IL-1beta, IL-6, and TNF-alpha levels in the culture medium. Conclusion The ability to simultaneously suppress the release of proinflammatory cytokines and PGE(2) may help control osteolysis and prevent aseptic loosening of THR. This effect could increase implant longevity and lead the way to the pharmacological treatment of this pathology.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2001

Structural transition and pair formation in Fe3O2BO3.

We observe for the first time a structural phase transition in the oxyborate Fe3O2BO3 which occurs along three leg ladders present in this material. X-ray diffraction shows that this transition at 283 K is associated with a new phase where atomic displacements occur in alternate directions perpendicular to the axis and within the plane of the ladders. Magnetic data show that these displacements lead to the formation of singlet pairs which dissociate close to the structural transition. Anomalies in the transport properties also occur close to 283 K showing that the structural transition is related to a charge ordering phenomenon in a low dimensional structure.

Journal Article↗

PubMed2001

In vivo dual inhibition of cyclooxygenase and lipoxygenase by ML-3000 reduces the progression of experimental osteoarthritis: suppression of collagenase 1 and interleukin-1beta synthesis.

OBJECTIVE: To study the therapeutic effectiveness of ML-3000, a new antiinflammatory drug that has balanced dual inhibitory activity against 5-lipoxygenase and cyclooxygenase, on the development of lesions in the experimental osteoarthritis (OA) dog model, and to determine the action of ML-3000 on the synthesis of collagenase 1 in cartilage and interleukin-1beta (IL-1beta) in synovial membrane. METHODS: The anterior cruciate ligament of the right stifle joint of 21 mongrel dogs was sectioned with a stab wound. Dogs were divided into 3 groups: group 1 (n = 7) received placebo; groups 2 (n = 7) and 3 (n = 7) were treated with therapeutic dosages of oral ML-3000 at 2.5 mg/kg/day and 5 mg/kg/day, respectively. The dogs began receiving medication the day after surgery and were killed 8 weeks later. The size and grade of cartilage erosions on both the condyles and plateaus were evaluated, and the severity of the cartilage lesions and synovial inflammation was examined histologically. Levels of collagenase 1 in cartilage and IL-1beta in the synovial membrane were measured by immunohistochemistry. In addition, levels of prostaglandin E2 (PGE2) in the synovial fluid and leukotriene B4 (LTB4) in cultured synovial membrane explants were determined using specific enzyme immunoassays. RESULTS: Serum levels of ML-3000 in treated dogs were within the therapeutic range. ML-3000 significantly decreased the size and grade of the cartilage lesions in tibials and plateaus, compared with placebo. At the histologic level, the severity of cartilage lesions was also decreased in the ML-3000-treated dogs versus the placebo-treated dogs in both the condyles and the plateaus. All 3 OA groups exhibited a notable and similar level of synovial inflammation. ML-3000 significantly decreased the level of PGE2 in synovial fluid and LTB4 production by synovium. It also markedly reduced the levels of collagenase 1 in cartilage and IL-1beta in synovial membrane. CONCLUSION: ML-3000 significantly reduced the development of lesions in experimental dog OA. The drug acts by reducing the synthesis of the inflammation mediators PGE2 and LTB4 and catabolic factors such as collagenase 1 and IL-1beta, which are known to play an important role in the pathophysiology of OA lesions. The effect of the drug on catabolic factors could possibly be related to its inhibitory action on LTB4 synthesis.

Acetates↗

PubMed2001

Endogenous prostaglandin E2 and insulin-like growth factor 1 can modulate the levels of parathyroid hormone receptor in human osteoarthritic osteoblasts.

Subchondral bone sclerosis may be important for the onset and/or progression of cartilage loss/damage in human osteoarthritis (OA). OA osteoblasts are resistant to parathyroid hormone (PTH) stimulation, which could explain bone sclerosis via the inhibition of PTH-dependent catabolism. Here, we investigated the molecular mechanism(s) responsible for reduced PTH-dependent cyclic adenosine monophosphate (cAMP) synthesis in OA subchondral osteoblasts. Although cholera toxin (CTX) increased basal cAMP formation in these cells, it failed to stimulate PTH-dependent cAMP synthesis, whereas pertussis toxin (PTX) did not inhibit basal cAMP, yet diminished PTH-dependent cAMP production. Binding of 125I-PTH indicated lower PTH receptor levels in OA than in normal osteoblasts (-50.5 +/- 9.5%). This could be attributed to either reduced expression of the PTH receptor (PTH-R) or altered recycling of existing pools of receptors. Reverse-transcription polymerase chain reaction (RT-PCR) analysis indicated decreased PTH-R messenger RNA (mRNA) levels in OA cells that were highly variable (ranging from -10% to -60%), a situation that reflects disease severity. Interestingly, OA osteoblasts produced more prostaglandin E2 (PGE2) than normal osteoblasts, and using naproxen, a cyclo-oxygenase inhibitor, increased PTH-dependent cAMP formation to a level similar to normal osteoblasts. Because heterologous desensitization can explain a decrease in PTH binding but cannot account for reduced PTH-R expression, we looked at the possible effect of insulin-like growth factor 1 (IGF-1) on this parameter. Blocking IGF-1 signaling with a neutralizing receptor antibody increased 125I-PTH binding in both normal and OA osteoblasts. Conversely, treatments with IGF-1 receptor (IGF-1R) antibody only slightly increased the levels of PTH-R mRNA whereas the addition of IGF-1 significantly reduced PTH-R mRNA levels (-24.1 +/- 7.1%), yet neither PGE2 nor naproxen modified PTH-R levels. These results suggest that both IGF-1 signaling and PGE2 formation repress PTH-dependent response in OA osteoblasts, a situation that can contribute to abnormal bone remodeling and bone sclerosis in OA.

Aged↗

PubMed2001

Tufted hair folliculitis after scalp injury.

We describe the case of a 38-year-old epileptic man with tufted hair folliculitis. The condition started 5 years ago after a scalp laceration that had been sustained 3 months earlier during an epileptic crisis. There then appeared a circumscribed inflammatory bulging lesion (with exudation and crusts) that evolved to scarring alopecia with tufts of 20 to 30 apparently normal hair shafts. Results of bacteriologic examination of pus extruding from the dilated follicular ostia revealed Staphylococcus aureus. The cutaneous pathologic examination showed polymorphous inflammatory exudate in the upper and mid dermis, which was mostly perifollicular, and the presence of normal and independent follicles in the deep dermis, which, while ascending, converged to a common dilated follicular channel. The patient was treated successively with oral flucloxacillin, erythromycin, ciprofloxacin, and amoxicillin/clavulanic acid and with topical application of erythromycin, clindamycin, povidone iodine, and ketoconazole. Transient improvement was followed by recurrence and enlargement of the affected area.

Adult↗

PubMed2001

Diacerein reduces the excess synthesis of bone remodeling factors by human osteoblast cells from osteoarthritic subchondral bone.

OBJECTIVE: Although cartilage degradation characterizes osteoarthritis (OA), there is evidence that remodeling of subchondral bone in this disease is a contributing factor. Therapeutic strategies to modify the metabolism of subchondral bone osteoblasts may be indicated to treat OA. We studied the effects of diacerein and rhein on the metabolic and inflammatory variables of OA subchondral osteoblasts. METHODS: Human OA primary subchondral osteoblast cells were used. The effect of diacerein and rhein at therapeutic concentrations (5-20 microg/ml) was determined by osteoblast phenotypic factors, alkaline phosphatase, osteocalcin, and cAMP; on metabolic agents urokinase plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), and insulin-like growth factor-1 (IGF-1); and on inflammatory mediators interleukin 6 (IL-6), prostaglandin E2 (PGE2), and cyclooxygenase-2 (COX-2). RESULTS: Diacerein and rhein did not affect either basal and 1,25(OH)2D3 induced alkaline phosphatase or parathyroid hormone (PTH) stimulated cAMP formation. Conversely, they dose dependently and statistically inhibited 1,25(OH)2D3 induced osteocalcin release, a situation explained by a reduction of mRNA levels for osteocalcin. Of the metabolic factors, they inhibited the production of uPA, with rhein showing slightly more potency; inhibitions of 69% and 57% were reached at the highest concentration (20 microg/ml) of rhein and diacerein, respectively. Both drugs also inhibited the PAI-1 level, albeit at a much lower level than for uPA. Interestingly, determination of the uPA/PAI1 ratio revealed that both drugs inhibited it about 55%, suggesting a decrease in uPA activity. In contrast, IGF-1 levels only increased slightly when cells were treated with rhein but not with diacerein. A transient dose dependent effect was found on IL-6 production; an inhibition was noted at low drug concentrations, which returned to basal levels at the highest concentration tested. PGE2 levels increased exponentially and were related to a concomitant increase in COX-2 levels in response to both drugs. CONCLUSION: Our data indicate that diacerein and rhein do not appear to affect OA subchondral bone cells' basal cellular metabolism, yet both agents reveal a direct effect at reducing the synthetic activities of osteoblasts, which could be responsible for abnormal subchondral bone remodeling occurring during the course of OA.

Aged↗

PubMed2001

Chondrocyte death in experimental osteoarthritis is mediated by MEK 1/2 and p38 pathways: role of cyclooxygenase-2 and inducible nitric oxide synthase.

OBJECTIVE: To explore the mechanisms responsible for in situ induction of chondrocyte death in experimental dog osteoarthritic (OA) cartilage. The roles of 2 mitogen activated protein kinases (MAPK), MEK 1/2 and p38, nuclear factor-kappaB (NF-kappaB), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and the caspase cascade were investigated. METHODS: OA knee cartilage was obtained from dogs that had received sectioning of the anterior cruciate ligament and were sacrificed 12 weeks after surgery. Cartilage explants were cultured in different inhibitors: Z-DEVD-FMK (caspase 3 inhibitor), Z-LEHD-FMK (caspase 9 inhibitor), PD 98059 (MEK 1/2 inhibitor). SB 202190 (p38 inhibitor), SN-50 (NF-kappaB inhibitor), NS-398 (COX-2 inhibitor), N-iminoethyl-l-lysine (L-NIL) (iNOS inhibitor). Cartilage specimens were stained for TUNEL reaction and immunostained using specific antibodies for caspase 3, COX-2, iNOS, and nitrotyrosine. Morphometric analyses were performed. RESULTS: The significant level of chondrocyte death in OA cartilage was markedly decreased by caspase 3 and caspase 9 inhibitors. The two MAPK inhibitors, but not the NF-kappaB inhibitor, decreased chondrocyte death concomitant with the levels of caspase 3 and iNOS. COX-2 level was reduced by all 3 inhibitors. Specific inhibition of either COX-2 or iNOS reduced the level of chondrocyte death and caspase 3. There was evidence of crosstalk between these 2 latter systems; specific inhibition of COX-2 reduced the iNOS level, and selective inhibition of iNOS reduced COX-2 expression. COX-2 and iNOS seem to function in a positive autoregulatory manner that triggers transcription of their own biosynthetic machinery, since the specific inhibition of each system downregulates its expression. CONCLUSION: This study shows that in the early lesions of experimental OA cartilage in situ, activation of the caspase cascade is responsible for induction of chondrocyte death. Marked inhibition of cell death by caspase inhibitors indicates a significant participation of apoptosis in the phenomenon. This phenomenon is linked to the activation of at least 2 major kinase pathways, MEK 1/2 and p38. These pathways are responsible for upregulating the expression of iNOS and COX-2, each of which seems essential for the induction of apoptosis. Data are provided about possible regulation and interregulation of the COX-2 and iNOS systems by prostaglandin E2 and NO.

Animals↗

PubMed2000

Selective inhibition of inducible nitric oxide synthase reduces progression of experimental osteoarthritis in vivo: possible link with the reduction in chondrocyte apoptosis and caspase 3 level.

OBJECTIVE: To evaluate the in vivo therapeutic efficacy of N-iminoethyl-L-lysine (L-NIL), a selective inhibitor of inducible nitric oxide synthase, on the progression of structural lesions in the experimental canine model of osteoarthritis (OA), and to explore the effect of L-NIL on the level of chondrocyte apoptosis and of important proteins involved in the apoptotic phenomenon, i.e., caspase 3 (inducer) and Bcl-2 (inhibitor). METHODS: The OA model was created by sectioning the anterior cruciate ligament. Dogs were placed into 4 experimental groups: unoperated dogs that received no treatment (controls), operated (OA) dogs that received placebo treatment, OA dogs that received oral L-NIL at 10 mg/kg/day, and OA dogs that received oral L-NIL at 1.0 mg/kg/day. In both L-NIL groups, treatment started immediately after surgery. The OA dogs were killed at 12 weeks after surgery. RESULTS: OA dogs treated with L-NIL showed a reduction in the size of osteophytes and a significant decrease in the severity of macroscopic and histologic cartilage lesions on both condyles and plateaus, compared with untreated OA dogs. L-NIL treatment also significantly decreased metalloprotease activity in cartilage. Immunohistochemical analysis revealed that the levels of chondrocyte apoptosis, caspase 3, and Bcl-2 were markedly increased in OA cartilage (P < 0.0001). A positive correlation between the levels of chondrocyte apoptosis and levels of caspase 3 was found (r = 0.54, P < 0.0001). OA dogs treated with the higher dosage L-NIL showed significantly reduced levels of chondrocyte apoptosis (P < 0.003) and caspase 3 (P < 0.04), but no effect on the increased level of Bcl-2 was demonstrated. CONCLUSION: This study shows that L-NIL reduces the progression of experimental OA. This effect could be related to a reduced level of chondrocyte apoptosis and is likely mediated by a decrease in the level of caspase 3 activity. A sparing effect of L-NIL on the increased level of Bcl-2 may also be a contributing factor.

Animals↗

PubMed2000

Gene therapy for osteoarthritis: new perspectives for the twenty-first century.

Morphologic changes observed in osteoarthritis include cartilage erosion and a variable degree of synovial inflammation. Proinflammatory cytokines such as interleukin-1 beta, locally produced by the inflamed synovium, also likely contribute to these alterations. Despite an extensive armamentarium and numerous surgical options, osteoarthritis remains incurable, and an improved approach in the treatment of this disease is imperative. Drug delivery is a major weakness of existing antiarthritic therapies. Local delivery of antiinflammatory cytokines or the in vivo induction of their expression using gene transfer may provide a novel approach for the treatment of osteoarthritis. Evidence of the efficacy of gene therapy in osteoarthritis remains very scarce. To the authors' knowledge, there is no clinical research protocol en route for the treatment of osteoarthritis using gene therapy. The authors present the only two studies that have proved successful in treating animal models of osteoarthritis using gene therapy, and propose an overview of several strategies for the development of gene therapy in osteoarthritis treatment in the future.

Animals↗

PubMed2000

Carprofen simultaneously reduces progression of morphological changes in cartilage and subchondral bone in experimental dog osteoarthritis.

OBJECTIVE: To examine the effect of a nonsteroidal antiinflammatory drug, carprofen, on the structure and metabolism of cartilage and subchondral bone in the experimental osteoarthritic (OA) canine model. METHODS: Experimental Groups 1 and 2 received a sectioning of the anterior cruciate ligament (ACL) of the right stifle joint, and were administered carprofen (2.2 and 4.4 mg/kg/twice daily/po, respectively) for 8 weeks beginning 4 weeks postsurgery. Group 3 received ACL sectioning and no treatment. Group 4 was composed of unoperated normal dogs. Cartilage macroscopic lesions were assessed, and their histological severity was graded. Specimens of subchondral bones were fixed, decalcified, and stained with hematoxylin/eosin. The level of metalloprotease (MMP) activity in cartilage was measured. Osteoblast cells were prepared from the subchondral bone. The level of synthesis of osteoblast biomarkers (osteocalcin, alkaline phosphatase), as well as urokinase plasminogen activator (uPA) activity and insulin-like growth factor (IGF-1) in the culture medium, was estimated. RESULTS: Carprofen treatment decreased the width of osteophytes (p < 0.01), the size of cartilage lesions, and the histologic severity of cartilage lesions (p < 0.008). There was no difference in the levels of MMP activity in cartilage between OA and carprofen treated groups. In OA dogs, the subchondral bone plate was thinner and was the site of an extensive remodeling process with numerous lacunae. Dogs treated with carprofen showed a marked decrease in the remodeling activity with normal plate thickness, and subchondral bone morphology resembling that of normal dogs. Osteoblasts from untreated OA dogs showed slightly higher alkaline phosphatase activities and osteocalcin release that reverted back to normal upon carprofen treatment. Moreover, uPA activity and IGF-1 levels were increased in OA dogs and were significantly reduced in carprofen treated dogs. CONCLUSION: Under therapeutic conditions, treatment with carprofen could reduce the progression of early structural changes in experimental OA. Carprofen treatment also delays and/or prevents the abnormal metabolism of subchondral osteoblasts in this model. The hypothesis of a possible link between the protective effect of carprofen and its effect on subchondral bone is of interest in the context of therapeutic intervention.

Alkaline Phosphatase↗

PubMed1999

Pharmacologic therapy of osteoarthritis.

This article presents a brief review of the most current therapies that are used for the relief of the symptoms related to osteoarthritis. The agents used either systematically or locally are described, providing the rationale for their usage in the treatment of osteoarthritis. Moreover, new therapies that have reached clinical evaluations and that can possibly reduce or stop the progression of the disease--namely the inhibitors of metalloproteases--are presented. Overall, it is obvious that significant progress has been made toward the development of new therapeutic agents to reduce the symptoms as well as the structural changes of the disease.

Adrenal Cortex Hormones↗