Between 1975 and the present, the history of vitamin D has been expanded through pivotal discoveries. These include the identification of active forms of vitamin D, signal transduction mechanisms, synthesis and degradation pathways and the understanding of vitamin D as an endocrine system:

The Vitamin D Receptor (VDR)

The discovery that vitamin D metabolites directly interact with chromatin marked a fundamental advance in vitamin D research: the identification of the vitamin D receptor (VDR). The VDR is a nuclear receptor that functions like a transcription factor and regulates a wide array of genes. Particularly affected are genes that play a central role in calcium and phosphate homeostasis, which are essential for maintaining stable mineral levels in the blood and ensuring normal bone development.

The VDR does not act in isolation: it works closely with co-activators and repressors that finely modulate gene expression. Through this interplay, the VDR can both activate and inhibit specific genes, allowing precise regulation of complex physiological processes. Interestingly, there is evidence that vitamin D also exerts non-genomic effects mediated by a membrane-bound VDR. This aspect is not yet fully characterized but suggests that vitamin D can act more rapidly than through classical gene regulation.

Vitamin D Binding Protein and Enzymes

Another central element in vitamin D metabolism is the vitamin D binding protein (DBP). This transport protein binds vitamin D and its metabolites in the blood, ensuring their stable circulation. DBP thus plays a crucial role in the availability of vitamin D for tissues and organs.

The conversion of vitamin D into its biologically active forms is controlled by a group of cytochrome P450 enzymes (CYPs). The most important members are:

• CYP2R1: 25-hydroxylase, which converts vitamin D into 25-hydroxyvitamin D₃ (25-OH-D₃), the main circulating form.

• CYP27B1: 1-hydroxylase, which converts 25-OH-D₃ into the hormonally active form 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂D₃).

• CYP24A1:  24-hydroxylase, which regulates the breakdown of vitamin D metabolites, ensuring homeostasis.

These enzymes have been isolated, cloned, and extensively studied in terms of function and regulation. They are crucial for the balance between active and inactive vitamin D forms and, therefore, for the physiological efficacy of the vitamin throughout the body.

Clinical Relevance

Defects in vitamin D metabolism can have serious health consequences. Vitamin D deficiency or genetic defects in the enzymes or the VDR can lead to diseases such as:

• Rickets:  A disorder primarily affecting children, leading to bone deformities.

• Vitamin D dependent rickets: Genetically caused disorders in which vitamin D cannot be properly activated.

• Hypercalcemia: Elevated blood calcium levels resulting from dysregulation of vitamin D metabolism.

Thanks to the discovery of active metabolites and the VDR, targeted therapies have been developed. Vitamin D analogs are now used to treat deficiency states or metabolic defects, especially in patients with chronic kidney disease, where the synthesis of the hormonally active form is impaired.

Significance for Modern Medicine

Research on vitamin D illustrates how scientific curiosity, experimental innovation and technological advances can revolutionize our understanding of biochemical processes. Today, vitamin D is far more than just a “bone vitamin”: it is an essential component of the endocrine system and influences numerous physiological processes, from mineral regulation to gene expression.

Insights into the VDR, vitamin D metabolites and enzymatic conversion pathways have enabled the development of novel therapies. These advances help treat diseases associated with disturbed vitamin D metabolism and improve health and quality of life worldwide. Vitamin D research remains a dynamic field, continuously providing new insights into molecular mechanisms and therapeutic opportunities.

With these findings, it can be said that the central story of the discovery and investigation of vitamin D is largely complete: it stands as an outstanding example of how systematic scientific work, curiosity and technological innovation can combine to achieve a profound understanding of a vital vitamin.

Sources: 

DeLuca, H. F. (2014). History of the discovery of vitamin D and its active metabolites. BoneKEy Reports, 3, 479. Source

Jones, G. (2022). 100 YEARS OF VITAMIN D: Historical aspects of vitamin D. Endocrine Connections, 11(4), e210594. Source