Pathway maps

Transcription_Role of VDR in regulation of genes involved in osteoporosis
Transcription_Role of VDR in regulation of genes involved in osteoporosis

Object List (links open in MetaCore):

CYP27B1, COL1A1, 1.14.-.-, CG alpha, Dexamethasone, PKC, ApoE, p57, 1alpha,23(S),25-trihydroxyvitamin D3, IL-1 beta, Carbonic anhydrase II, FasL(TNFSF6), Osteopontin, TRPC3, VDR, SMAD3, Osteocalcin, TGF-beta receptor type I, Ca('2+) extracellular region, IFN-gamma, None, C-Jun/C-Fos, TNF-alpha, GCR-alpha, IGF-1, Cortisol, 1.14.13.13, RANKL(TNFSF11), 1.14.14.1, Calcitonin receptor, Osteoprotegerin, CYP3A4, Calcitriol, RANK (TNFRSF11A), Calreticulin, FRA-1, IL-6, Calcifediol cytoplasm, CDX2, PKA-cat (cAMP-dependent), CALB1, 6beta- hydroxydexamethasone, C-Fos, IL-1 alpha, CYP24A1, CYP19, Parathyroid hormone, C-Jun, RXRA, Calcitonin, Ca('2) cytosol, Thyroid hormone receptor, 1.14.14.1, Androgen receptor, Galpha(q)-specific parathyroid hormone GPCRs, 6beta- hydroxycortisol, RUNX2

Description

Role of VDR in regulation of genes involved in osteoporosis

Osteoporosis is a common disease affecting the majority of older women and a significant minority of older men. It is defined as the gradual reduction in bone strength with advancing age, particularly in post-menopause women. Osteoporosis is one of the major and growing health care problems around the world. One of the first genes to be associated with the common form of osteoporosis is that for the Vitamin D receptor ( VDR ) [1]. This gene encodes the nuclear hormone receptor for vitamin D3 belonging to the family of trans-acting transcriptional regulatory factors. VDR is activated by active form of vitamin D - Calcitriol. Calcitriol is produced in the kidneys via CYP27B1 by conversion from Calcifediol.

VDR downstream targets are principally involved in mineral metabolism. The effects of the vitamin D system on calcium and bone homeostasis are largely mediated by promoting active intestinal calcium transport via the induction of the epithelial calcium channel - Transient receptor potential cation channel, subfamily V, member 6 ( TRPV6 ) [2]. The accumulation of intracellular calcium generated by the constitutively open TRPV6 channels, however, impairs further calcium transport activity of these channels unless this intracellular free calcium is buffered by proteins such as Calbindin ( CALB1 ). Transcription of CALB1 is positively regulated by VDR.

Many essential and typical osteoblast genes are shown to be highly regulated by VDR including RUNX2, Type I collagen alpha 1 ( COL1A1 ), Osteopontin, Osteocalcin. VDR stimulates Ligand for receptor activator of nuclear factor kappaB ( RANKL )/ Receptor activator of nuclear factor kappaB ( RANK ) -mediated osteoclastogenesis and bone resorption through up-regulation of RANKL [2]. Osteoclast-mediated bone resorption could be inhibited by Osteoprotegerin ( OPG ) which binds RANKL to prevent association with its receptor [3].

References:

  1. Eisman JA
    Genetics of osteoporosis. Endocrine reviews 1999 Dec;20(6):788-804
  2. Bouillon R, Verstuyf A, Mathieu C, Van Cromphaut S, Masuyama R, Dehaes P, Carmeliet G
    Vitamin D resistance. Best practice & research. Clinical endocrinology & metabolism 2006 Dec;20(4):627-45
  3. Vitovski S, Phillips JS, Sayers J, Croucher PI
    Investigating the Interaction between Osteoprotegerin and Receptor Activator of NF-{kappa}B or Tumor Necrosis Factor-related Apoptosis-inducing Ligand: EVIDENCE FOR A PIVOTAL ROLE FOR OSTEOPROTEGERIN IN REGULATING TWO DISTINCT PATHWAYS. The Journal of biological chemistry 2007 Oct 26;282(43):31601-9