agn-190121 and Disease-Models--Animal

Retinoids are natural and synthetic analogues of the hormone retinoic acid. Systemic retinoid agonist therapy is usually associated with toxic side effects, such as mucocutaneous toxicity, which may be alleviated by the use of topical retinoid antagonists. We report the synthesis and biological activity of a new series of potent, RAR-specific antagonists substituted with phenylcyclohexene and phenylcyclohexadiene groups.

Topics: Animals; Benzoates; Cyclohexanes; Dermatitis, Irritant; Disease Models, Animal; Mice; Receptors, Retinoic Acid; Retinoids

Vitamin A and its derivatives (retinoids) have been known to cause premature epiphyseal closure in humans as an unwanted side effect of chronic treatment. The purpose of the present study was to determine if guinea pigs could serve as an animal model of retinoid-induced epiphyseal plate closure, and to utilize this model to study the mechanism. Weanling male Hartley guinea pigs were treated ip via osmotic pump for up to 14 days with vehicle or 0.50 to 5.5 mg/kg/day of the retinoic acid receptor (RAR)-selective agonist AGN 190121. Histopathological examination of the proximal tibia of AGN 190121-treated guinea pigs revealed a dose-dependent disruption of the epiphyseal plate. The natural retinoids all-trans-retinoic acid and 13-cis-retinoic acid also induced epiphyseal plate closure in guinea pigs when administered by ip injection for 10 days. Prominent histological features of retinoid-induced epiphyseal closure included the loss of basophilic staining in the extracellular matrix of epiphyseal plate chondrocytes and the invasion of the epiphyseal plate by osteoclasts. To determine if the epiphyseal closure detected histologically was reversible, guinea pigs were treated for 6 days with the RAR-selective agonist (E)-4[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propen- 1-y1]benzoic acid (TTNPB) or vehicle, and groups of guinea pigs were euthanized on Day 7 or 57. TTNPB but not vehicle treatment caused histological evidence of epiphyseal closure at both time points, and significant bone elongation between Day 7 and Day 57 was detected only in vehicle-treated animals. Epiphyseal closure and other toxic effects of TTNPB were blocked by cotreatment of guinea pigs with a fivefold molar excess of AGN 193109, an RAR antagonist. Taken together, these data demonstrate the utility of the guinea pig as an animal model of retinoid-induced epiphyseal closure and suggest that RAR activation is necessary and sufficient for this activity.

Topics: Animals; Benzoates; Disease Models, Animal; Growth Plate; Guinea Pigs; Isotretinoin; Male; Receptors, Retinoic Acid; Tretinoin