tretinoin and Calcinosis

The synthetic retinoids, the vitamin-D-derivatives etretinate and isotretinoin, have substantially enlarged the therapeutic arsenal in dermatology. They are primarily used in severe cases of acne and cornification disorders. In the majority of cases, long-term treatment is necessary. Certain side effects in the skeletal system can occur, e.g., osteoporosis, premature epiphyseal closure, and changes similar to DISH (diffuse idiopathic skeletal hyperostosis). We discuss the reports in the literature and our own observations in 31 patients treated at the Westphalian Wilhelms University in Muenster, as well as at the Technical University in Munich. In 3 out of 31 patients treated by retinoids on a long-term basis, skeletal changes were found radiologically as a result of the retinoid medication.

Topics: Adolescent; Adult; Calcinosis; Child; Etretinate; Female; Humans; Hyperostosis, Diffuse Idiopathic Skeletal; Isotretinoin; Male; Middle Aged; Osteoporosis; Radiography; Skin Diseases; Spinal Osteophytosis; Time Factors; Tretinoin

Topics: Alkalosis; Benzothiadiazines; Calcinosis; Cholecalciferol; Diuretics; Humans; Hypercalcemia; Hyperparathyroidism; Isotretinoin; Lithium; Osteitis Deformans; Sarcoidosis; Sodium Chloride Symporter Inhibitors; Tamoxifen; Tretinoin; Vitamin A

Topics: Baths; Calcinosis; Cat-Scratch Disease; Child; Diabetes Mellitus, Type 1; Folliculitis; Foot Dermatoses; Herpes Simplex; Humans; Hyperhidrosis; Isomerism; Isotretinoin; Joint Diseases; Lyme Disease; Skin Diseases; Tinea; Tretinoin

To evaluate the therapeutic effect of all-trans retinoic acid (ATRA) with and without cytosine arabinoside in relapsing malignant gliomas.. 9 patients (8 male, 1 female, age 53.9 +/- 11.2) with relapsing malignant gliomas (grade IV:6; grade III:3) were treated by ATRA 1 to 21 months after the end of their initial treatment. ATRA was given unceasingly during 2 to 17 months at 90 mg/d. In 6 patients it was associated to cytosine arabinoside (4 g/course, 1 to 9 courses every 4 weeks).. 4 non-responder patients died 2.5 to 4 months after starting therapy. One patient who had been reoperated before receiving ATRA and cytosine arabinoside (5 course) had no sign of tumor recurrence after 17 months of treatment. In 4 responder patients (2 glioblastoma and 2 anaplastic astrocytoma) a clinical and radiological stabilization (time to progression) during 9 +/- 2.5 months was observed. This stabilization was associated in 3 of them with the appearance of intra tumoral calcifications visualized on repeated CT scans and confirmed in one patient by post-mortem examination. All of them had received cytosine arabinoside (1 to 9 courses) with ATRA; however small calcifications were also observed in one non-responder patient who did not receive aracytine.. These results suggest: a) a therapeutic effect of ATRA in combination with cytosine arabinoside in patients with relapsing malignant gliomas b) that intratumoral calcifications are related to the effects of ATRA on differentiation and/or on endothelial t-PA production and that these effects explain the tumor progression arrest in responder patients. The transient efficiency is probably related to the pharmacokinetics of ATRA or to changes of cellular mechanisms that modulate the cell response to the drug and is a critical issue for this therapy.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Astrocytoma; Brain Neoplasms; Calcinosis; Cytarabine; Disease Progression; Female; Glioblastoma; Glioma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Recurrence, Local; Radiography; Time Factors; Tretinoin

The blood testis-barrier (BTB) is essential for maintaining homeostasis in the seminiferous epithelium. Although many studies have reported that vitamin A (VA) is required for the maintenance of spermatogenesis, the relationships between the BTB, spermatogenesis and VA have not been elucidated. In this study, we analyzed BTB assembly and spermatogenesis in the testes of mice fed the VA-deficient (VAD) diet from the prepubertal period to adulthood. During the prepubertal period, no changes were observed in the initiation and progression of the first spermatogenic wave in mice fed the VAD diet. However, the numbers of preleptotene/leptotene spermatocytes derived from the second spermatogenic wave onwards were decreased, and initial BTB formation was also delayed, as evidenced by the decreased expression of mRNAs encoding BTB components and VA signaling molecules. From 60 days postpartum, mice fed the VAD diet exhibited apoptosis of germ cells, arrest of meiosis, disruption of the BTB, and dramatically decreased testis size. Furthermore, vacuolization and calcification were observed in the seminiferous epithelium of adult mice fed the VAD diet. Re-initiation of spermatogenesis by VA replenishment in adult mice fed the VAD diet rescued BTB assembly after when the second spermatogenic wave initiated from the arrested spermatogonia reached the preleptotene/leptotene spermatocytes. These results suggested that BTB integrity was regulated by VA metabolism with meiotic progression and that the impermeable BTB was required for persistent spermatogenesis rather than meiotic initiation. In conclusion, consumption of the VAD diet led to critical defects in spermatogenesis progression and altered the dynamics of BTB assembly.

Topics: Animals; Apoptosis; Biomarkers; Blood-Testis Barrier; Calcinosis; Diet; Disease Models, Animal; Epididymis; Female; Gene Expression Regulation, Developmental; Infertility, Male; Male; Metaplasia; Mice; Mice, Inbred C57BL; Organ Size; Spermatogenesis; Spermatogonia; Testis; Tretinoin; Vacuoles; Vitamin A Deficiency

Calcific aortic valve disease (CAVD) is a major public health problem with no effective treatment available other than surgery. We previously showed that mature heart valves calcify in response to retinoic acid (RA) treatment through downregulation of the SRY transcription factor Sox9. In this study, we investigated the effects of excess vitamin A and its metabolite RA on heart valve structure and function in vivo and examined the molecular mechanisms of RA signaling during the calcification process in vitro.. Using a combination of approaches, we defined calcific aortic valve disease pathogenesis in mice fed 200 IU/g and 20 IU/g of retinyl palmitate for 12 months at molecular, cellular, and functional levels. We show that mice fed excess vitamin A develop aortic valve stenosis and leaflet calcification associated with increased expression of osteogenic genes and decreased expression of cartilaginous markers. Using a pharmacological approach, we show that RA-mediated Sox9 repression and calcification is regulated by classical RA signaling and requires both RA and retinoid X receptors.. Our studies demonstrate that excess vitamin A dietary intake promotes heart valve calcification in vivo. Therefore suggesting that hypervitaminosis A could serve as a new risk factor of calcific aortic valve disease in the human population.

Topics: Animals; Aortic Valve; Calcinosis; Cell Line; Chick Embryo; Collagen Type II; Dietary Supplements; Disease Models, Animal; Diterpenes; Gene Expression Profiling; Gene Expression Regulation; Heart Valve Diseases; Hypervitaminosis A; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Osteogenesis; Osteopontin; Receptors, Retinoic Acid; Retinoid X Receptors; Retinyl Esters; RNA Interference; Signal Transduction; SOX9 Transcription Factor; Time Factors; Tissue Culture Techniques; Transfection; Tretinoin; Vitamin A; Vitamins

Calcification of heart valve structures is the most common form of valvular disease and is characterized by the appearance of bone-like phenotypes within affected structures. Despite the clinical significance, the underlying etiology of disease onset and progression is largely unknown and valve replacement remains the most effective treatment. The SRY-related transcription factor Sox9 is expressed in developing and mature heart valves, and its function is required for expression of cartilage-associated proteins, similar to its role in chondrogenesis. In addition to cartilage-associated defects, mice with reduced sox9 function develop skeletal bone prematurely; however, the ability of sox9 deficiency to promote ectopic osteogenic phenotypes in heart valves has not been examined.. This study aims to determine the role of Sox9 in maintaining connective tissue homeostasis in mature heart valves using in vivo and in vitro approaches.. Using histological and molecular analyses, we report that, from 3 months of age, Sox9(fl/+);Col2a1-cre mice develop calcific lesions in heart valve leaflets associated with increased expression of bone-related genes and activation of inflammation and matrix remodeling processes. Consistently, ectopic calcification is also observed following direct knockdown of Sox9 in heart valves in vitro. Furthermore, we show that retinoic acid treatment in mature heart valves is sufficient to promote calcific processes in vitro, which can be attenuated by Sox9 overexpression.. This study provides insight into the molecular mechanisms of heart valve calcification and identifies reduced Sox9 function as a potential genetic basis for calcific valvular disease.

Topics: Age Factors; Aging; Animals; Animals, Newborn; Calcinosis; Calcium; Chick Embryo; Collagen Type II; Disease Models, Animal; Down-Regulation; Extracellular Matrix; Female; Gene Knockdown Techniques; Genotype; Heart Valve Diseases; Inflammation; Integrases; Male; Mice; Mice, Transgenic; Mitral Valve; Osteogenesis; Phenotype; SOX9 Transcription Factor; Tissue Culture Techniques; Transfection; Tretinoin; Tricuspid Valve

Matrix gamma-carboxyglutamic acid protein (MGP), a vitamin K-dependent protein, is involved in regulation of tissue calcification. We previously reported that 9-cis retinoic acid (RA) mitigates 1alpha,25-dihydroxycholecalciferol [1,25(OH)(2)D3]-induced renal calcification in a 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung cancer A/J male mouse model. This raised the question if the mechanism(s) underlying this calcification involves vitamin K. We assessed expression and vitamin K dependent gamma-carboxylation of MGP and vitamin K concentrations [phylloquinone (PK), as well as its conversion product, menaquinone-4 (MK-4)] in tissues obtained from NNK-injected A/J male mice fed 1,25(OH)(2)D3 (2.5 microg/kg diet; D group) +/- RA (15 mg/kg diet) for 20 wk. Renal calcification was only observed in the D group (2/10; 20% of the group). Renal MGP mRNA and uncarboxylated MGP (ucMGP) increased in response to D (P < 0.05) but not in response to RA or RA + D. In contrast, gamma-carboxylated MGP increased to 2.2-fold of the control in response to D+RA (P < 0.05) but not in response to RA or D alone. Although all diets contained equal amounts of PK, the kidney MK-4 concentration was higher in the D group (P < 0.05) and lower in the RA group (P < 0.05) compared with the RA+D or control groups. Renal PK concentrations were lower in the RA and RA+D groups than in the control and D groups (P < 0.05). These data suggest that 9-cis RA mitigated 1,25(OH)(2)D3-induced renal calcification by modifying the 1,25(OH)(2)D3-induced increase in ucMGP. The mechanisms by which 9-cis RA and 1,25(OH)(2)D3 alter vitamin K concentrations warrant further investigation.

Topics: Alitretinoin; Animals; Base Sequence; Calcinosis; Calcitriol; Calcium-Binding Proteins; Carbon-Carbon Ligases; Carcinogens; Dietary Supplements; DNA Primers; Extracellular Matrix Proteins; Kidney Diseases; Liver; Male; Matrix Gla Protein; Mice; Mice, Inbred A; Nitrosamines; RNA, Messenger; Tretinoin; Vitamin K

We report here a comparative study of the development and behavior of chondrocytes isolated from normal growth plate tissue, tibial dyschondroplasic lesions, and from articular cartilage. The objective of these studies was to determine whether the properties exhibited by chondrocytes in dysplasic lesions or in articular cartilage were due to their cellular phenotype, their environment, or both. We had previously analyzed the electrolytes and amino acid levels in the extracellular fluid of avian growth plate chondrocytes. Using these data, we constructed a culture medium (DATP5) in which growth plate cells essentially recapitulate their normal behavior in vivo. Here, we used DATP5 to examine the behavior of chondrocytes isolated from lesions of tibial dyschondroplasia (TD). We found that once isolated from lesion and grown in this supportive medium, dysplasic chondrocytes behaved essentially like normal growth plate cells. These findings suggest that the cause of TD is local factors operating in vivo to prevent these cells from developing normally. With respect to articular chondrocytes, our data indicate that they more closely retain normal protein and proteoglycan synthesis when grown in serum-free media. These cells readily induced mineral formation in vitro, both in the presence and absence of serum. However, in serum-containing media, mineralization was significantly enhanced when the cells were exposed to retinoic acid (RA) or osteogenic protein-1 (OP-1). Our studies support previous work indicating the presence of autocrine factors produced by articular chondrocytes in vivo that prevent mineralization and preserve matrix integrity. The lack of inhibitory factors and the presence of supporting factors are likely reasons for the induction of mineralization by articular chondrocytes in vitro.

Topics: Animals; Autocrine Communication; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcification, Physiologic; Calcinosis; Cartilage, Articular; Cell Differentiation; Cells, Cultured; Chickens; Chondrocytes; Chondrogenesis; Culture Media; Culture Media, Serum-Free; Growth Plate; Osteochondrodysplasias; Proteoglycans; Tibia; Transforming Growth Factor beta; Tretinoin

Altered chondrocyte differentiation, including development of chondrocyte hypertrophy, mediates osteoarthritis and pathologic articular cartilage matrix calcification. Similar changes in endochondral chondrocyte differentiation are essential for physiologic growth plate mineralization. In both articular and growth plate cartilages, chondrocyte hypertrophy is associated with up-regulated expression of certain protein-crosslinking enzymes (transglutaminases (TGs)) including the unique dual-functioning TG and GTPase TG2. Here, we tested if TG2 directly mediates the development of chondrocyte hypertrophic differentiation. To do so, we employed normal bovine chondrocytes and mouse knee chondrocytes from recently described TG2 knockout mice, which are phenotypically normal. We treated chondrocytes with the osteoarthritis mediator IL-1 beta, with the all-trans form of retinoic acid (ATRA), which promotes endochondral chondrocyte hypertrophy and pathologic calcification, and with C-type natriuretic peptide, an essential factor in endochondral development. IL-1 beta and ATRA induced TG transamidation activity and calcification in wild-type but not in TG2 (-/-) mouse knee chondrocytes. In addition, ATRA induced multiple features of hypertrophic differentiation (including type X collagen, alkaline phosphatase, and MMP-13), and these effects required TG2. Significantly, TG2 (-/-) chondrocytes lost the capacity for ATRA-induced expression of Cbfa1, a transcription factor necessary for ATRA-induced chondrocyte hypertrophy. Finally, C-type natriuretic peptide, which did not modulate TG activity, comparably promoted Cbfa1 expression and hypertrophy (without associated calcification) in TG2 (+/+) and TG2 (-/-) chondrocytes. Thus, distinct TG2-independent and TG2-dependent mechanisms promote Cbfa1 expression, articular chondrocyte hypertrophy, and calcification. TG2 is a potential site for intervention in pathologic calcification promoted by IL-1 beta and ATRA.

Topics: Alkaline Phosphatase; Animals; Calcinosis; Cartilage, Articular; Cattle; Cells, Cultured; Chondrocytes; Collagen Type X; Collagenases; Core Binding Factor Alpha 1 Subunit; Extremities; Gene Expression; GTP-Binding Proteins; Hypertrophy; Interleukin-1; Matrix Metalloproteinase 13; Mice; Mice, Inbred C57BL; Mice, Knockout; Natriuretic Peptide, C-Type; Neoplasm Proteins; Osteoarthritis; Protein Glutamine gamma Glutamyltransferase 2; Transcription Factors; Transglutaminases; Tretinoin

Matrix Gla Protein (MGP) is a small protein which is thought to be an inhibitor of tissue calcification and a regulator of cell differentiation. In this study we have examined the transcriptional regulation of MGP within rat vascular smooth muscle cells (VSMCs). We found that MGP transcription is downregulated by retinoic acid and transforming growth factor beta (TGF beta) whereas it is upregulated by vitamin D3 and cyclic AMP.

Topics: Animals; Arteriosclerosis; Calcinosis; Calcium-Binding Proteins; Cholecalciferol; Cyclic AMP; Down-Regulation; Extracellular Matrix Proteins; Gene Expression Regulation; Humans; Matrix Gla Protein; Muscle, Smooth, Vascular; Rats; Transcription, Genetic; Transforming Growth Factor beta; Tretinoin; Up-Regulation

Topical preparations of tretinoin are used for the treatment of various skin conditions and for rejuvenation of the skin. Published information on pregnancy outcome following maternal exposure to topical tretinoin is limited to three case reports. We report a case of a patient with anomalies involving the ear and central nervous system with exposure to topical tretinoin during the first trimester. Though the potential link between the use of topical tretinoin and the existence of fetal malformations remains to be further documented by animal as well as epidemiological studies, we strongly recommend that the use of topical tretinoin during pregnancy should be discouraged, and effective contraception should be used in patients of childbearing age.

Topics: Administration, Topical; Brain; Calcinosis; Contraindications; Ear; Female; Humans; Infant, Newborn; Keratolytic Agents; Male; Posterior Cerebral Artery; Pregnancy; Pregnancy Trimester, First; Tretinoin

Topics: Adult; Calcinosis; Central Nervous System Diseases; Fatal Outcome; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Male; Recurrence; 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

Topics: Aged; Calcinosis; Corneal Diseases; Dry Eye Syndromes; Female; Humans; Male; Tretinoin

Isotretinoin, a synthetic retinoid that has been prescribed for over 500,000 patients with cystic acne, has been associated with both spinal hyperostosis and a disorder similar to diffuse idiopathic skeletal hyperostosis. We describe a syndrome of tendon and ligament calcification, primarily in extraspinal locations, that we have observed after long-term therapy for psoriasis and disorders of keratinization with etretinate, another synthetic retinoid. Of 38 patients who had received etretinate (average dose, 0.8 mg per kilogram of body weight per day; average duration, 60 months), 32 (84 percent) had radiographic evidence of extraspinal tendon and ligament calcification. The most common sites of involvement were the ankles (29 patients [76 percent]), pelvis (20 patients [53 percent]), and knees (16 patients [42 percent]); spine involvement was uncommon in this group of etretinate-treated patients. Involvement tended to be bilateral and multifocal. Fifteen (47 percent) of the 32 affected patients had no bone or joint symptoms at the sites of radiographic abnormality. Thus, tendon and ligament calcification can occur without vertebral involvement as well as in association with it (for example, as part of the spectrum of diffuse idiopathic skeletal hyperostosis). We have identified extraspinal tendon and ligament calcification as a toxic effect that is commonly associated with long-term etretinate therapy.

Topics: Adult; Aged; Calcinosis; Etretinate; Female; Humans; Isotretinoin; Knee Joint; Ligaments; Lupus Erythematosus, Systemic; Male; Middle Aged; Pelvis; Prospective Studies; Psoriasis; Radiography; Skin Diseases; Spinal Diseases; Tendons; Tretinoin

Frequent symptoms of back and neck stiffness led to a radiographic investigation of the vertebral spine in patients receiving synthetic retinoids, isotretinoin and etretinate. X-ray examination of fifty patients with various skin disorders who received retinoids for at least 2 years were compared with seventy-two age- and sex-matched untreated patients. Differences in frequencies of defined abnormalities, which included anterior spinal ligament calcification and presence of osteophyte at two or more vertebral levels in the absence of joint space narrowing, were determined for treated and untreated patients. When the entire group of treated patients was compared with the entire group of those untreated, no statistically significant differences were observed. When only patients with basal cell nevus syndrome ( BCNS ) or basal cell carcinoma (BCC) who had never received retinoid were compared with those who received isotretinoin, the frequency of the defined abnormalities was significantly higher in the treated group (P less than 0.01). This study suggests that the ingestion of isotretinoin at mean total dose of 150,060 mg for an average of 2.9 years is associated with a statistically significant increase in developing an associated ossifying diathesis in patients with BCNS or BCC, when compared with matched, untreated controls.

Topics: Adult; Calcinosis; Dose-Response Relationship, Drug; Etretinate; Female; Humans; Isotretinoin; Male; Middle Aged; Radiography; Skin Diseases; Spinal Diseases; Spinal Osteophytosis; Spine; Tretinoin