1,25(OH)2D3-modulated calcium induced keratinocyte differentiation

Keratinocytes produce vitamin D3, metabolize it to its most biologically active form, 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), and respond to the 1,25(OH)2D3 they produce with a decrease in proliferation and an increase in differentiation. 1,25(OH)2D3 production by keratinocytes is tightly controlled and changes as the cells differentiate, increasing during the early stages of differentiation, then decreasing again as terminal differentiation ensues. The 1,25(OH)2D3 produced endogenously or supplied exogenously acts in concert with calcium to stimulate the transition from a proliferating basal cell to a terminally differentiated corneocyte. The mRNA levels for proteins involved in the differentiation process are controlled not only by calcium- and 1,25(OH)2D3-induced increase in gene transcription, but by subsequent calcium- and 1,25(OH)2D3-induced destabilization of the mRNA after adequate levels of the proteins have been produced. 1,25(OH)2D3 increases intracellular calcium in part by inducing phospholipase C, which when activated by hormones, cleaves phosphoinositol bisphosphate into two important signaling molecules inositol tris phosphate and diacylglycerol. Inositol tris phosphate releases intracellular calcium from intracellular stores, and the increase in intracellular calcium opens up the nonspecific cation channel through which calcium enters the cell. Diacylglycerol and intracellular calcium promote protein kinase C activity that can further enhance the differentiation process. These actions of 1,25(OH)2D3 provide the rationale for the effectiveness of 1,25(OH)2D3 and its analogs in psoriasis.