Action of Topical Thyroid Hormone Analogues on Glucocorticoid-Induced Skin Atrophy in Mice

Abstract

Previously we demonstrated the stimulation of collagen synthesis in triiodothyroacetic acid (TRIAC)-topically treated human and mice. In the present study, we have evaluated the dose response effect of thyroid hormone (TH) analogues and tretinoin on glucocorticoid-induced skin atrophy in a haired mouse model. For this investigation, we treated haired mice twice daily for 7 days with various topically administered doses of TRIAC, triiodothyronine-sodium salt (T(3)-Na), diiodothyroacetic acid (DIAC), 3,5-diiodothyropropionic acid (DITPA), and tretinoin with 0.2 mM betamethasone17-valerate (BM), or with the vehicle as a control group. We also investigated a combination of commercial betamethasone dipropionate (BD) 0.05% cream and various doses of TRIAC on mouse skin. TRIAC was able to reverse the skin atrophy by 25% in a daily dose of 1 nmol/cm(2) in the presence of 0.2 mM BM (p < 0.05). Neither other TH analogues nor TRIAC in lower and higher concentrations had a significant inhibitory effect on dermal atrophy (p > 0.05). A combination of 0.2 mM BM and 10 nmol/cm(2) TRIAC was able to prevent dermal atrophy by 18%. The addition of TRIAC to 0.05% BD cream in a final concentration of 0.1% was able partially to reverse the dermal atrophy by 15% (p < 0.05). TRIAC alone in a concentration of 1,000 nmol/cm(2) stimulated dermal proliferation by 34% (p < 0.05). Other TH analogues alone had no stimulatory effect on dermal proliferation. Tretinoin 0.8 mM was able to inhibit dermal atrophy by 20% (p < 0.05) and had an effect on dermal thickness of 85% (p < 0.05). However, severe side effects with edema, erythema, and scaling were commonly observed in all tretinoin-treated mouse skin, which could partly explain the increase in dermal thickness. In contrast, no skin side effects were observed after treatment with TRIAC. This study indicates that TRIAC may have a therapeutic effect on BM-induced dermal atrophy in mouse skin and a direct stimulatory effect on dermal proliferation when given alone.

Thyroid Hormone Analogue Stimulates Keratinocyte Proliferation but Inhibits Cell Differentiation in Epidermis

“…Previous studies on mice and humans have confirmed that TRIAC is safe when applied topically to the skin (6)(7)(8).…”

“…Recent work has highlighted their potential contributions to glucocorticoid-induced skin atrophy and wound repair (3)(4)(5)(6)(7)(8). However, the functions of THs in controlling the balance between cell proliferation and cell differentiation in the skin have proven to be puzzling.…”

Action of Topical Thyroid Hormone Analogue, Triiodothyroacetic Acid in Reversing Glucocorticoid-Induced Skin Atrophy in Humans

“…TRIAC is a natural metabolite of T 3 with the amino group and methylene group removed from the alanine side chain (26). Previous studies in mice and humans have confirmed that TRIAC is safe when applied topically to the skin (28)(29)(30)(31). Additionally, no significant effect on serum thyroid hormone levels with topical TRIAC was observed (28,30).…”

“…However, information relating to the mechanism of action of TH in fibroblasts, especially when it comes to the regulation of collagen production, is limited (22). Studies in mice and humans have shown that topical triiodothyronine (T 3 ) and triiodothyroacetic acid (TRIAC) increase dermal collagen production, epidermal thickness, and dermal proliferation (23)(24)(25)(26)(27)(28)(29). TRIAC is a natural metabolite of T 3 with the amino group and methylene group removed from the alanine side chain (26).…”

Triiodothyroacetic acid in health and disease

“…Topical application of TA 3 increases dermal thickness and prevents glucocorticoid-induced skin atrophy in mice and humans (Faergemann et al 2002, Yazdanparast et al 2006a, and stimulates procollagen synthesis and keratinocyte proliferation in human skin (Yazdanparast et al 2004, Zhang et al 2012, but has no beneficial effects on plaque psoriasis (Vahlquist et al 2004). …”