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Vitamin D action: lessons from VDR and Cyp27b1 null mice
Roger Bouillon1, Liesbet Lieben, Chantal Mathieu
1Clinical and Experimental Endocrinology, KU Leuven, Herestraat 49 ON1 bus 902, 300 Leuven, Belgium. roger.bouillon@med.kuleuven.be
Abstract:
Even one century after its discovery, there are still many gaps in the understanding of the vitamin D endocrine system. Inactivation of the vitamin D receptor (VDR) or the enzymes metabolizing its ligand (especially Cyp27bl) in mice has clearly demonstrated that the active form of vitamin D [1,25(OH)2D] is essential to stimulate calcium absorption in the gut during normal/low calcium intake, and as a consequence, that 1,25(OH)2D is required to maintain normal serum calcium, bone and growth plate homeostasis. These findings have resulted in clear clinical guidelines for the treatment of vitamin D-related bone diseases of infants, children and adults. Tissue-specific VDR or Cyp27b1 deletion in mice has also proven to be useful to define the precise role of 1,25(OH)2D action in cells belonging to the intestine, bone, growth plate and also to many non-classical target tissues. Indeed, experimental findings show that 1,25(OH)2D has numerous extraskeletal effects, and observational studies in man demonstrate that disturbances in the vitamin D pathway are associated with major human diseases such as cancer, infections, autoimmune diseases, cardiovascular and metabolic diseases, muscle function, reproduction and neurocognitive disorders. We will compare the findings in VDR- and Cyp27bi-null mice with findings in man to elucidate what is presently understood of the vitamin D endocrine system and to identify the still outstanding questions.
Insights
The active form of vitamin D [1,25(OH)2D] is crucial for calcium absorption and bone health. Research in mice and humans reveals its essential role in skeletal homeostasis and extraskeletal functions, highlighting ongoing research needs.
Area of Science:
- Endocrinology
- Molecular Biology
- Nutritional Science
Background:
- The vitamin D endocrine system's full function remains incompletely understood a century after discovery.
- The active form of vitamin D, 1,25(OH)2D, is known to be essential for calcium absorption and skeletal homeostasis.
Purpose of the Study:
- To compare findings in VDR- and Cyp27b1-null mice with human data.
- To elucidate current understanding of the vitamin D endocrine system.
- To identify outstanding questions regarding vitamin D's roles.
Main Methods:
- Utilizing genetically modified mice with inactivated vitamin D receptor (VDR) or key metabolizing enzymes (Cyp27b1).
- Comparing experimental findings in mice with observational studies in humans.
- Analyzing the impact of 1,25(OH)2D on classical (gut, bone) and non-classical target tissues.
Main Results:
- Inactivation studies confirm 1,25(OH)2D's necessity for intestinal calcium absorption and maintenance of serum calcium, bone, and growth plate homeostasis.
- Tissue-specific gene deletion models reveal precise roles of 1,25(OH)2D in various tissues.
- Human studies link vitamin D pathway disturbances to extraskeletal diseases, including cancer, infections, autoimmune, cardiovascular, metabolic, and neurocognitive disorders.
Conclusions:
- The active form of vitamin D is indispensable for skeletal health and has widespread extraskeletal effects.
- Significant knowledge gaps persist regarding the vitamin D endocrine system's complete physiological and pathological roles.
- Further research is needed to fully understand vitamin D's impact on human health and disease.
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