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Vitamin D is mainly produced in the skin (cholecalciferol) by sun exposure while a fraction of it is obtained from dietary sources (ergocalciferol). Vitamin D is further processed to 25-hydroxyvitamin D and 1,25-dihydroxy vitamin D (calcitriol) in the liver and kidneys, respectively. Calcitriol is the active form which mediates the actions of vitamin D via vitamin D receptor (VDR) which is present ubiquitously. Defect at any level in this pathway leads to vitamin D deficient or resistant rickets. Nutritional vitamin D deficiency is the leading cause of rickets and osteomalacia worldwide and responds well to vitamin D supplementation. Inherited disorders of vitamin D metabolism (vitamin D-dependent rickets, VDDR) account for a small proportion of calcipenic rickets/osteomalacia. Defective 1α hydroxylation of vitamin D, 25 hydroxylation of vitamin D, and vitamin D receptor result in VDDR1A, VDDR1B and VDDR2A, respectively whereas defective binding of vitamin D to vitamin D response element due to overexpression of heterogeneous nuclear ribonucleoprotein and accelerated vitamin D metabolism cause VDDR2B and VDDR3, respectively. Impaired dietary calcium absorption and consequent calcium deficiency increases parathyroid hormone in these disorders resulting in phosphaturia and hypophosphatemia. Hypophosphatemia is a common feature of all these disorders, though not a sine-qua-non and leads to hypomineralisation of the bone and myopathy. Improvement in hypophosphatemia is one of the earliest markers of response to vitamin D supplementation in nutritional rickets/osteomalacia and the lack of such a response should prompt evaluation for inherited forms of rickets/osteomalacia., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The vitamin D signal transduction system involves a series of cytochrome P450-containing sterol hydroxylases to generate and degrade the active hormone, 1α,25-dihydroxyvitamin D3, which serves as a ligand for the vitamin D receptor-mediated transcriptional gene expression described in companion articles in this review series. This review updates our current knowledge of the specific anabolic cytochrome P450s involved in 25- and 1α-hydroxylation, as well as the catabolic cytochrome P450 involved in 24- and 23-hydroxylation steps, which are believed to initiate inactivation of the vitamin D molecule. We focus on the biochemical properties of these enzymes; key residues in their active sites derived from crystal structures and mutagenesis studies; the physiological roles of these enzymes as determined by animal knockout studies and human genetic diseases; and the regulation of these different cytochrome P450s by extracellular ions and peptide modulators. We highlight the importance of these cytochrome P450s in the pathogenesis of kidney disease, metabolic bone disease, and hyperproliferative diseases, such as psoriasis and cancer; as well as explore potential future developments in the field.

Rickets refers to deficient mineralization at the growth plate and is usually associated with abnormal serum calcium and/or phosphate. There are several subtypes of rickets, including hypophosphatemic rickets (vitamin-D-resistant rickets secondary to renal phosphate wasting), vitamin D-dependent rickets (defects of vitamin D metabolism) and nutritional rickets (caused by dietary deficiency of vitamin D, and/or calcium, and/or phosphate). Most rickets manifest as bone deformities, bone pain, and impaired growth velocity. Diagnosis of rickets is established through the medical history, physical examination, biochemical tests and radiographs. It is of crucial importance to determine the cause of rickets, including the molecular characterization in case of vitamin D resistant rickets, and initiate rapidly the appropriate therapy. In this review, we describe the different causes and therapies of genetic and nutritional rickets, supported by the recent progress in genetics and development of novel molecules such as anti-FGF23 antibody., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The vitamin D signal transduction system involves a series of cytochrome P450-containing sterol hydroxylases to generate and degrade the active hormone, 1α,25-dihydroxyvitamin D3, which serves as a ligand for the vitamin D receptor-mediated transcriptional gene expression described in companion articles in this review series. This review updates our current knowledge of the specific anabolic cytochrome P450s involved in 25- and 1α-hydroxylation, as well as the catabolic cytochrome P450 involved in 24- and 23-hydroxylation steps, which are believed to initiate inactivation of the vitamin D molecule. We focus on the biochemical properties of these enzymes; key residues in their active sites derived from crystal structures and mutagenesis studies; the physiological roles of these enzymes as determined by animal knockout studies and human genetic diseases; and the regulation of these different cytochrome P450s by extracellular ions and peptide modulators. We highlight the importance of these cytochrome P450s in the pathogenesis of kidney disease, metabolic bone disease, and hyperproliferative diseases, such as psoriasis and cancer; as well as explore potential future developments in the field.