Epithelial differentiation, retinoids

Ciubotariu, D., Grozav, A., Gogonea, V., Ciubotariu, C., Medeleanu, M., Dragos, D., Pasere, M. and Simon, Z. (2001) The effects of retinoids upon epithelial differentiation of hamster trachea, induction of ornithine decarboxylase and promotion of tumors in mouse epidermis. A QSAR study by MTD method. MATCH Commun. Math. Comput. Chem., 44, 65-92. 

Retinoids include natural compounds and synthetic derivatives of retinol that exhibit vitamin A activity. Retinoids have many important functions throughout the body, including roles in vision, regulation of cell proliferation and differentiation, and bone growth, immune defense, and tumor suppression. Because vitamin A affects normal epithelial differentiation, it was investigated as a treatment for cutaneous disorders but was abandoned initially because of unfavorable side effects. Molecular modifications yielded compounds with vastly improved margins of safety. 

Although it appears that the isomerization of all-rra s-retinoic acid to the 13-cis isomer is a physiological event, the importance of this step is not known. The 13-cw-retinoic acid is equivalent in biological activity to all-rrans-retinoic acid, both in vivo (Zile and DeLuca, 1968) and in vitro (Newton et al., 1980). More work is needed, however, before it can be determined whether isomerization of retinoids might be an important event in the control of epithelial differentiation as has already been shown to be the case for the visual cycle. 

Numerous studies have demonstrated that degradation products of (3-carotene exhibit deleterious effects in cellular systems (Alija et al., 2004, 2006 Hurst et al., 2005 Salerno et al., 2005 Siems et al., 2003). A mixture of (3-carotene degradation products exerts pro-apoptotic effects and cytotoxicity to human neutrophils (Salerno et al., 2005 Siems et al., 2003), and enhances the geno-toxic effects of oxidative stress in primary rat hepatocytes (Alija et al., 2004, 2006), as well as dramatically reduces mitochondrial activity in a human leukaemic cell line, K562, and RPE 28 SV4 cell line derived from stably transformed fetal human retinal pigmented epithelial cells (Hurst et al., 2005). As a result of degradation or enzymatic cleavage of (3-carotene, retinoids are formed, which are powerful modulators of cell proliferation, differentiation, and apoptosis (Blomhoff and Blomhoff, 2006). 

Gorodeski GI, Eckert RL, Utian WH, Sheean L, and Rorke EA [1990] Cultured human ectocervical epithelial cell differentiation is regulated by the combined direct actions of sex steroids, glucocorticoids and retinoids. J Clin Endocrinol Metab 70 1624-1630... 

Sizemore N, Kasturi L, Gorodeski G, Eckert RL, Jetten AM, and Rorke EA [1993] Retinoid regulation of human ectocervical epithelial cell transglutaminase activity and keratin gene expression. Differentiation 54 219-225... 

Agarwal C, Chandraratna RAS, Teng M, Nagpal S, Rorke EA, and Eckert RL [1996] Differential regulation of human ectocervical epithelial cell line proliferation and differentiation by retinoid x receptor- and retinoic acid receptor-specific retinoids. Cell Growth Differentiation 7 521-530... 

Agarwal C, Rorke EA, Irwin JC, and Eckert RL [1991] Immortalization by human papillomavirus type 16 alters retinoid regulation of human ectocervical epithelial cell differentiation. Cancer Res 51 3982-3989... 

Jetten, A. M., and Smits, H. (1985). Regulation of differentiation of tracheal epithelial cells by retinoids. Ciba Found. Symp. 113, 61-76. 

Mechanism of Action A retinoid that decreases cohesiveness of follicular epithelial cells. Increases turnover of follicular epithelial cells. Bacterial skin counts are not altered. Transdermal Exerts its effects on growth and differentiation of epithelial cells. Antineoplastic Induces maturation, decreases proliferation of acute promyelocytic leukemia (APL) cells. Therapeutic Effect Causes expulsion of blackheads alleviates fine wrinkles, hyperpigmentation causes repopulation of bone marrow and blood by normal hematopoietic cells. 

They have been found to be active in the regulation and differentiation of many cell types, including epithelial. Therefore, many natural retinoids have been tested therapeutically against skin diseases, including some forms of malignancies. 

Vitamin A (retinol) is a key regulator of epithelial ceU proliferation and differentiation. Aberrations in these processes are a feature of many skin diseases, and dermatologists have therefore long taken an interest in vitamin A as a therapeutic agent. However, marginal efficacy and unacceptable adverse effects (Table 1) have minimized the usefulness of vitamin A itself. Therefore, derivatives of vitamin A (retinoids) have been developed. 

H]Retinoic acid-treated human tracheobronchial epithelial cells contained several polar retinoic acid metabolites that coeluted with 4-oxo-, 4-hydroxy-, and 18-hydroxy-retinoic acid (Kim et al. 2000). 4-Hydroxy-retinoic acid could effectively induce MUC2 and MUC5AC mRNA expression in human tracheobronchial epithelial cells, indicating that it is an active retinoid able to induce mucous cell differentiation. 

Retinoids are known for their importance in general growth, the growth and differentiation of epithelial tissues, visual function, and reproduction. The mechanism by which retinoids manifest all their biological effects is largely unknown. To facilitate additional basic research on the biochemistry and pharmacology of... 

Jetten, A. M, Nervi, C, and Vollberg, T M (1992) Control of squamous differentiation in tracheobronchial and epidermal epithelial cells, role of retinoids J. Natl, Cancer Inst Monog. 13, 93-100. 

Retinoids have been shown to exert effects on differentiation of both epithelial cells (keratinocytes) and mesenchymal cells (chondrocytes, adipocytes, and hematopoetic cells) in eulture, much as had been observed both in vivo (Wolbach and Howe, 1925) and in organ culture in vitro (see previous section). In certain other cells, only growth and not differentiation is affected. Whether both types of effects have a common basis will have to await mechanistic studies. 

The experiments of Lotan et al. (1982a) showed decreases in the poly(A)+RNA population of S91 melanoma cells cultured for 5 days in the presence of 10 retinoic acid as compared to controls. Such treatment results in nearly 90% inhibition of the growth of the cells. Protein synthesis by these cells was depressed relative to control cultures, as evidenced not only by the decreased poly(A) + RNA levels but also by decreases in the proportions of ribosomes in polysomes and decreases in polysome-associated mRNA. In contrast to the effects of Omori and Chytil (1982) on a differentiating epithelial tissue, Lotan et al. (1982a) found little qualitative differences in the protein patterns of treated or control cells. Further experiments should help answer the question of whether the underlying mechanisms of retinoid control of growth and differentiation are distinct or identical. 

---