Vitamin D was discovered originally as an antirachitic agent. The development of new therapies for treatment and prevention of bone mass loss depends on a full understanding of the molecular mechanisms by which osteoblasts produce and secrete bone, and how these processes are regulated by hormones such as vitamin D. Here I review studies on non-ge- nomic, membrane-initiated molecular mechanisms of secretion of bone materials in single, live osteoblasts. We utilize techniques of high spatial-temporal resolution applied to individual osteoblasts in culture such as patch-clamp electrophysiology and confocal microscopy. The biologically active 1a,25(OH)2– vitamin D3 (1,25D) potentiates chloride and calcium channel activities within minutes through mechanisms that involve signal transduction pathways and develop only in the presence of a functional vitamin D receptor. Secretory activities are coupled to 1,25D-activation of ion channels and elevation of cytoplasmic calcium, and lead to bone matrix production. Although the primary focus of this review is on basic research, the long-term objective of our work is to identify molecular targets in the treatment of bone pathologies characterized by decreased bone mass and mineralization. This typifies skeletal diseases such as osteoporosis and osteomalacia, respectively. Osteoporosis in particular affects a large sector of the aging population and constitutes a significant financial burden for the society.
Vitamin D and bone
Bone anabolic effects of 1,25D comprise matrix production and mineralization. In osteoblasts, the bone-forming cells, activation of bone matrix protein synthesis by 1,25D occurs via the nuclear vitamin D receptor (VDR), which modulates gene transcription. In addition, 1,25D exerts non- genomic effects in osteoblasts. Known as rapid actions, they have been described for different steroids. Rapid actions are characterized by: 1) developing within seconds to minutes, which excludes the possibility of new mRNA and protein synthesis; 2) insensitivity to inhibitors of gene transcription and protein synthesis, and 3) appear in response to steroids bound to large molecules such as BSA, which prevents them from entering the cell. In osteoblasts, rapid non-genomic 1,25D actions are characterized by: a) activation of intracellular signal transduction pathways, b) elevation of cytoplasmic Ca2+ concentration, and c) potentiation of ion channel activities. However, the physiological significance of these rapid, membrane-initiated effects of 1,25D in bone cells remains a field relatively unexplored. Your life is worth living. online
It has been known for over a century that vitamin D deficiency leads to rickets and osteomalacia, characterized by bone lesions and deformities from inadequate mineralization. In addition, dietary calcium and vitamin D supplementation have proven to be effective in the treatment of osteoporosis, a disease characterized by bone mass loss. A number of effects have been described when primary osteoblasts or osteoblastic cell lines are treated with 1,25D in vitro. By acting on the VDR in the cell nucleus, 1,25D modulates the expression of genes associated with osteoblast differentiation and bone production, such as alkaline phosphatase, type I collagen, and non-collagenous proteins. In addition, 1,25D stimulates mineralization in cultures of osteoblast-like cell lines. Some research groups postulate indirect effects of vitamin D metabolites on bone formation, mainly centered around the idea that 1,25D acts primarily on calcium intestinal absorption and delivery of calcium to the bone. In fact, the effect of 1,25D on bone in vivo appears to be a combination of direct actions on bone cells and indirect actions to regulate calcium absorption and delivery to the bone.