tretinoin and Arthritis

Disease modifying antirheumatic drugs (DMARDs) have improved the prognosis of autoimmune inflammatory arthritides but a large fraction of patients display partial or nonresponsiveness to front-line DMARDs. Here, an immunoregulatory approach based on sustained joint-localized release of all-trans retinoic acid (ATRA), which modulates local immune activation and enhances disease-protective T cells and leads to systemic disease control is reported. ATRA imprints a unique chromatin landscape in T cells, which is associated with an enhancement in the differentiation of naïve T cells into anti-inflammatory regulatory T cells (T

Topics: Animals; Antirheumatic Agents; Arthritis; Autoimmune Diseases; Inflammation; Mice; T-Lymphocytes, Regulatory; Tretinoin

A disintegrin and metalloprotease with thrombospondin domains (ADAMTS)-4 (aggrecanase-1) and ADAMTS-5 (aggrecanase-2) are metalloproteases involved in articular cartilage degradation and represent potential therapeutic targets in arthritis treatment. We explore herein the ability of different natural compounds to specifically block the destructive action of these enzymes. Following a preliminary screening using carboxymethylated transferrin as substrate, we focused our interest on luteolin due to its inhibitory effect on ADAMTS-4 and ADAMTS-5 activities using aggrecan and fluorogenic peptides as substrates. However, matrix metalloproteinases (MMPs) activities on these substrates result less affected by this flavonoid. Moreover, incubation of mouse chondrogenic ATDC5 cells in the presence of luteolin clearly decreases the release of aggrecan fragments mediated by aggrecanases under the same conditions in which aggrecanolysis mediated by MMPs is detected. Additionally, glycosaminoglycan levels in culture medium of murine cartilage explants stimulated with interleukin-1-alpha plus retinoic acid are reduced by the presence of the flavonoid. This inhibition takes place through blockade of ADAMTS-mediated aggrecanolysis, while MMPs activity is not or poorly affected. These results suggest that luteolin could be employed as a prototypic modifying disease-agent to create new chondroprotective compounds aimed to specifically block the unwanted aggrecanase activities in arthritic diseases.

Topics: ADAM Proteins; ADAMTS4 Protein; ADAMTS5 Protein; Aggrecans; Animals; Arthritis; Cartilage, Articular; Cells, Cultured; Chondrocytes; Endopeptidases; Extracellular Matrix Proteins; Glycosaminoglycans; Interleukin-1alpha; Luteolin; Matrix Metalloproteinases; Metalloproteases; Mice; Procollagen N-Endopeptidase; Tretinoin

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Biomarkers; DNA Mutational Analysis; Gene Expression Regulation, Enzymologic; Genetic Predisposition to Disease; Homocysteine; Humans; Hyperhomocysteinemia; Keratolytic Agents; Low Back Pain; Male; Methionine; Methylenetetrahydrofolate Reductase (NADPH2); Muscle Cramp; Muscle, Skeletal; Mutation; Radiography; Sacroiliac Joint; Sulfasalazine; Tretinoin

Abnormal metabolism of extracellular inorganic pyrophosphate (PPi) by articular cartilage contributes to calcium pyrophosphate dihydrate (CPPD) crystal formation and the resultant arthritis known as CPPD deposition disease. The factors causing excess PPi elaboration in affected cartilage remain poorly defined. Retinoic acid (RA), a naturally occurring vitamin A metabolite, promotes cartilage degeneration and mineralization, two correlates of CPPD crystal deposition. RA was examined as a potential modifier of cartilage PPi elaboration. All-trans RA (200-1000 nM) increased PPi levels in culture medium of normal porcine cartilage and chondrocytes 2-3-fold over control values at 96 hours of incubation (P < 0.01). IGF1 and anti-EGF antibody diminished the effects of RA on PPi elaboration. RA modestly increased activity of the PPi-generating ectoenzyme NTPPPH in culture medium (P < 0.01). As some RA effects are mediated through increased activity of TGFbeta, a known PPi stimulant, we examined the effect of anti-TGFbeta antibody on RA-induced PPi elaboration. PPi levels in medium were reduced from 30 +/- 7 microM in cartilage cultures with 500 nM RA to 14 +/- 4 microM PPi in cartilage cultures with RA and anti-TGFbeta. Anti-TGFbeta antibody, however, had no significant effect on RA-induced PPi elaboration in chondrocyte cultures. Thus, RA, along with TGFbeta and ascorbate, can now be included in the list of known PPi stimulants. All three of these factors promote mineralization in growth plate cartilage. These data support a central role for TGFbeta in CPPD disease, and provide further evidence linking processes of normal and pathologic calcification in cartilage.

Topics: Animals; Antibodies, Monoclonal; Arthritis; Calcinosis; Calcium Pyrophosphate; Cartilage, Articular; Cells, Cultured; Insulin-Like Growth Factor I; Keratolytic Agents; Knee Joint; Organ Culture Techniques; Pyrophosphatases; Swine; Transforming Growth Factor beta; Tretinoin

Prophylactic treatment (p.o.) of rats with adjuvant-induced arthritis (AA) with two retinoid-like 2,4,6,8-nonatetraenoic acids (NTA), Ro 23-6457 and Ro 23-2895, significantly reduced hind paw swelling between days 10-23 and the level of plasma fibrinogen (MED approximately 25 mumoles/kg). When given therapeutically (75 mumoles/kg between day 21 and 28) either NTA arrested the progression of the disease (MED, 25-75 mumoles/kg). Unseparated and adherent cell (AC) depleted spleen cells from rats with AA (day 12-15) responded poorly to the T cell mitogen, Con A (2.5 micrograms/ml) and the B cell mitogen, LPS (10 micrograms/ml). The responses were partially restored (approximately 30% of normal responses) in AC-depleted (but not unseparated) spleen cells from Ro 23-6457 treated rats (75 and 250 mumoles/kg/day). These data demonstrate an immunomodulatory effect of Ro 23-6457 in the adjuvant rat which may contribute to its anti-inflammatory activity in AA.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Arthritis, Experimental; Body Weight; Cell Division; Fibrinogen; Immunosuppressive Agents; Male; Mitogens; Rats; Tretinoin

Polymorphonuclear leukocytes contain proteases that are capable of degrading articular cartilage matrix in disease states such as rheumatoid arthritis and osteoarthritis. In this study, the HL-60 human promyelocytic leukemia cell line was examined for ability to degrade cartilage proteoglycans. The HL-60 cells contained proteoglycan-degrading enzymes, which may contribute to the joint inflammation sometimes seen in acute leukemia. However, the protease activity was much less than in mature neutrophils and was not enhanced by the induction of myeloid maturation with dimethyl sulfoxide or retinoic acid. The diminished enzyme activity of induced HL-60 cells compared to normal neutrophils is another functional deficiency of these cells.

Topics: Animals; Arthritis; Cartilage; Cattle; Cell Line; Dimethyl Sulfoxide; Humans; Leukemia, Myeloid, Acute; Neutrophils; Peptide Hydrolases; Proteoglycans; Tretinoin

Topics: Acne Vulgaris; Acute Disease; Adult; Arthritis; Humans; Isotretinoin; Male; Tretinoin

We studied the effects of oral administration of the retinoid, 4-hydroxyphenyl retinamide (4-HPR), on group A streptococcal cell wall-induced polyarthritis in the rat, a model characterized initially by exudative inflammation of peripheral joints followed by chronic proliferative/erosive synovitis. Experimental arthritis was induced in female LEW/N rats by i.p. injection of streptococcal cell walls in saline (15 micrograms/g body weight). Depending upon the experiment, continuous daily oral administration of the retinoid was begun either 14 days prior to induction of the disease, at the time of cell wall administration and/or 11 days and 31 days after cell wall injection. Dosage was either 1 or 2 mmol 4-HPR/kg of chow. During the course of the disease, severity of clinical illness was assessed by determination of clinical severity index, by histological or radiologic examination, and by measurement of production in vitro of collagenase and prostaglandin E2 by excised synovial tissue. In rats fed the retinoid prior to cell wall injection, both the acute and the chronic responses were suppressed. In rats given the retinoid at the time of cell wall injection, the acute inflammatory response was only partially suppressed on the diet containing 2 mmol 4-HPR/kg chow, but the chronic disease was impressively inhibited in a dose dependent manner. Similarly, in animals with established disease, the drug was also effective; however, the more advanced the illness, the less effective the drug. Clinical observations were paralleled by the histological, radiographical and biochemical analyses. Treated animals showed far less synovial proliferation and joint destruction, and synovial tissues taken from these rats produced lesser amounts of collagenase and prostaglandin E2. No significant toxicity of the retinoid was noted. We conclude that oral administration of 4-HPR suppresses, in a dose and time dependent manner, both the acute and chronic stages of streptococcal cell wall-induced arthritis in rats without apparent significant toxicity. Our data suggest that studies of the effects of this retinoid on patients with chronic inflammatory synovitis are warranted.

Topics: Animals; Arthritis; Cell Wall; Dinoprostone; Disease Models, Animal; Female; Fenretinide; Granuloma; Liver Diseases; Microbial Collagenase; Prostaglandins E; Rats; Rats, Inbred Lew; Streptococcus pyogenes; Tretinoin

The induction of ceruloplasmin and metallothionein was investigated in rats with the early inflammatory phase of adjuvant arthritis. When examined at the peak of the acute inflammatory response, 5 days after adjuvant treatment, zinc given daily (2 mg/kg, intraperitoneally) increased serum ceruloplasmin levels by 2.0 times that found in nonarthritic rats and 1.2 times that found in non-zinc-treated arthritic rats. 13-cis-Retinoic acid (160 mg/kg, orally) given daily increased serum ceruloplasmin 2.2 and 2.7 times that found in nontreated arthritic rats when given alone and with zinc (2 mg/kg, intraperitoneally), respectively. Reduction in the inflammatory response was measured by weight of the adjuvant-injected paw, 5 days after adjuvant was administered. The reduction in inflammation was 13 and 19-20% for 13-cis-retinoic acid and zinc, respectively, when given alone, and between 26 and 31% when the treatments were combined. Zinc markedly increased liver metallothionein levels whereas 13-cis-retinoic acid was a much less potent inducer of the protein in liver. The results are discussed in light of the probable physiological roles of both ceruloplasmin and metallothionein.

Topics: Animals; Arthritis; Arthritis, Experimental; Ceruloplasmin; Isotretinoin; Male; Metallothionein; Rats; Rats, Inbred Strains; Tretinoin; Zinc

Topics: Acne Vulgaris; Adolescent; Arthritis; Diseases in Twins; Female; Humans; Isotretinoin; Male; Pregnancy; Tretinoin; Twins, Monozygotic

Treatment with isotretinoin (retinoic acid), which is frequently used in the control of acne, is associated with transient arthralgias in up to 16% of patients. We encountered two cases of acute, aseptic arthritis of the knee in male patients receiving isotretinoin, during the third week and third month of therapy. Synovial fluid obtained from one of the patients was noninflammatory. The drug concentration in the synovial fluid was 131 ng/mL--a level that was compatible with diffusion from the blood (simultaneous serum concentration, 229 ng/mL). Arthritis resolved in both patients without sequelae, despite continuation of drug treatment in one of them. This observation indicates that arthritis with joint effusion may complicate isotretinoin use; it also suggests that alternative measures should be considered before administering the drug to patients with rheumatologic disorders.

Topics: Acne Vulgaris; Acute Disease; Adult; Arthritis; Humans; Isotretinoin; Male; Tretinoin

Oral administration of 13-cis-retinoic acid (40 or 160 milligrams per kilogram of body weight daily) significantly reduced the inflammation associated with developing and established adjuvant arthritis, an experimentally induced arthritis in rats that resembles human rheumatoid arthritis. The amount of collagenase secreted in tissue culture by adherent cells isolated from the inflamed joints of adjuvant rats treated with 13-cis-retinoic acid also decreased as compared to the amount secreted by cells from vehicle-treated adjuvant rats. Collagenase is important in the joint destruction accompanying rheumatoid arthritis. The successful use of retinoids in the treatment of this proliferative but nonmalignant disorder demonstrates a new application of these compounds.

Topics: Animals; Arthritis; Arthritis, Experimental; Female; Fibrinogen; Inflammation; Male; Microbial Collagenase; Prostaglandins E; Rats; Sex Factors; Tretinoin

Clinical, general laboratory evaluation and immunological studies were conducted in 13 patients with active psoriatic arthropathy undergoing long-term treatment with aromatic retinoid (ethyl-all-trans-9-) (4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenate (Ro 10-9359). Evaluations were made at the beginning of treatment and at 3 and 6 months following drug therapy. A significant improvement in the clinical and laboratory parameters of inflammation was noted. In addition, immunological studies revealed certain changes suggesting that the treatment with Ro 10-9359 may effect some basic mechanisms of etiopathogenic significance in this disease. However, some undesirable, mostly dose-dependent adverse reactions affecting the muco-cutaneous tissues limit a wide use of this agent.

Topics: Adult; Arthritis; Etretinate; Humans; Ibuprofen; Immunoglobulins; Lymphocytes; Male; Middle Aged; Psoriasis; Tretinoin

We evaluated the effect of administering orally two synthetic analogues of retinoic acid, 13-cis-retinoic acid and all-trans-N-(4-hydroxyphenyl)-retinamide to age-matched female Sprague-Dawley rats immunized with native chick type II collagen in incomplete Freund's adjuvant. Ingestion of a diet containing 13-cis-retinoic acid was associated with a significant increase in the severity of collagen arthritis, but there was no effect on weight gain or hemagglutinating antibody titers and delayed-type hypersensitivity to type II collagen. In two separate trials, ingestion of 4-hydroxyphenyl retinamide also significantly enhanced the severity of arthritis. Monolayer cultures of dissociated synovial cells taken from arthritic rats, but not nonarthritic rats, released prostaglandin E2 (PGE2) and collagenase into the medium. The level of PGE2 production was significantly decreased by in vivo or in vitro exposure to 4-hydroxyphenyl retinamide, whereas the addition of 13-cis-retinoic acid to the cultures had no effect on PGE2 release by the arthritic synovial cells. Five rats fed the 13-cis-retinoic acid-containing diet for 5 mo did not develop clinical or histologic evidence of arthritis. These data demonstrate that both retinoids possess potent enhancing properties for an experimentally inducible autoimmune arthritis, that synovial cells produce PGE2 and collagenase in this model, and that production of PGE2 can be suppressed by 4-hydroxyphenyl retinamide.

Topics: Animals; Arthritis; Arthritis, Experimental; Collagen; Dose-Response Relationship, Drug; Female; Prostaglandins E; Rats; Structure-Activity Relationship; Time Factors; Tretinoin

Topics: Arthritis; Drug Therapy, Combination; Etretinate; Furocoumarins; Humans; Photochemotherapy; Psoriasis; Tretinoin

Four patients with active seronegative psoriatic arthropathy were treated with retinoid (Ro 10-9359) in a daily dose of 30 mg for at least four months. Within the first 4--6 weeks of treatment all patients showed marked improvement of arthritis as measured by the number of swollen joints, the Ritchie joint index, morning stiffness and the pain experienced. One patient stopped taking her concomitant medication of nonsteroidal anti-inflammatory agent, while the others were able to reduce the intake of such drugs substantially. None of the patients were taking steroids. The elevated erythrocyte sedimentation rate observed in all patients studied also fell gradually in the course of treatment. With the exception of dry lips observed in two patients, other adverse effect such as extensive mucosa dryness and cheilitis, as commonly seen in patients receiving this agent, were not recorded. In view of these encouraging preliminary results we are now conducting a multicenter control study to substantiate these findings.

Topics: Adult; Aged; Arthritis; Drug Evaluation; Etretinate; Humans; Middle Aged; Pilot Projects; Psoriasis; Tretinoin