Vitamin D plays an essential role in skeletal metabolism by binding to its nuclear steroid receptor, the vitamin D receptor (VDR). The heritability of bone mineral density (BMD) is well established, and the VDR gene is considered a prime candidate suggested to partially account for genetically controlled BMD variance in the population. The aim of a recent study was to reconstruct common haplotypes in the VDR 3’ untranslated region (UTR) and studied the association to BMD and risk of vertebral fractures in 3014 elderly men from Sweden and 2000 in Hong Kong, all participants of the global MrOS Study. To assess any functional implications of the VDR polymorphisms, the authors studied allele-specific expressions of the different VDR 3’ UTR haplotypes in the normal chromosomal context of 70 unrelated human trabecular bone samples. This was performed by quantitative genotyping of coding polymorphisms in RNA samples and in corresponding DNA samples isolated from the bone samples.
Osteoclasts (OCs) are large multinucleated cells of hematopoietic origin formed by the differentiation and fusion of mononuclear monocyte–macrophage lineage precursors after stimulation by RANKL and macrophage colony-stimulating factor (M-CSF). OC access to the bone surface requires precursor recruitment from the circulation into bone and a capacity to migrate to find their way to suitable stromal sites for their development into bone-resorptive mature multinucleated OCs (MMOCs). Mononucleated osteoclasts precursors (pre-OCs) have the capacity to transmigrate through endothelial cells. MMOCs also exhibit several features usually involved in cell invasion such as expression of the proto-oncogene c-src. Disruption of c-src leads to osteopetrosis in mice, resulting in the excessive accumulation of bone matrix caused by defective OC functions. Matrix metalloproteinases (MMPs), which play a major role in tumor cell invasion and metastasis, are also involved in OC function by promoting their recruitment and the degradation of the mineralized bone matrix. Finally, OCs exhibit podosomes, highly dynamic actin-rich structures involved in adhesion, migration, and matrix degradation, and sealing zones insuring attachment to bone surface.
Osteopetrosis is a genetically and clinically heterogeneous bone disorder characterized by a reduction in bone resorption and a generalized net accumulation of skeletal mass. The causative genes identified so far all play a role in acidification of the resorption lacuna, and loss-of-function mutations in these genes severely affect mature osteoclast function. The CA2 (carbonic anhydrase 2) gene produces the protons necessary for acidification of the resorption lacuna, the extracellular compartment between the bone tissue and the osteoclast where bone resorption occurs. The α3 subunit of the H+ ATPase is involved in the transportation of these protons through the ruffled border into the resorption lacuna, while chloride channel 7 (ClC-7) translocates chloride ions to maintain electroneutrality.
Pathological role of osteoclast costimulation in arthritis-induced bone loss
22/04/2008 in PathophysiologyOsteoclasts, multinucleated cells of hematopoietic origin that degrade the bone matrix, are regulated by immunoregulatory molecules under both physiological and pathological conditions. Combined deficiency of Fc receptor common γsubunit (FcRγ) and DNAX-activation protein 12 (DAP12) results in a complete lack of osteoclasts. In addition to RANK, the receptor for RANK ligand (RANKL), the Ig-like receptors associated with FcRγ and DAP12 have been recognized as essential receptors for osteoclastogenesis. This observation established that Ig-like receptors function as osteoclast costimulatory receptors, which are crucial for bone homeostasis under physiological conditions.
Bone metastases are a frequent complication of many cancers that result in severe disease burden and pain. It is now acknowledged that the microenvironment of the local host tissue actively participates in the propensity of certain cancers to metastasize to specific organs, and that bone provides an especially fertile ’soil’. In the case of breast cancers, the local chemokine milieu is now emerging as an explanation for why these tumors preferentially metastasize to certain organs. However, as the inhibition of chemokine receptors in vivo only partially blocks metastatic behavior, other factors must exist that regulate the preferential metastasis of breast cancer cells.
Patients with a variety of tumors, including those with breast cancer, are often treated with granulocyte-monocyte colony stimulating factor (GM-CSF), a cytokine that increases white cell counts. GM-CSF stimulates the proliferation and differentiation of hematopoietic precursors, thereby replenishing blood cells ravaged by chemotherapy.
Vitamin D receptor polymorphism is associated with fracture risk in older women
12/02/2008 in PathophysiologyThe active form of vitamin D, calcitriol, is essential to bone turnover and remodeling and to calcium-phosphate homeostasis. Alterations in the vitamin D endocrine system may contribute to bone loss with aging. One hypothesis proposes that age-related bone loss results from decreased intestinal absorption of calcium, leading to increased PTH, which, in turn, increases the rates of bone remodeling and bone loss. Decreases in the production of 1,25(OH)2 vitamin D, intestinal responsiveness to 1,25(OH)2 vitamin D, and levels of 25(OH) vitamin D may all contribute to the decreased intestinal absorption of calcium and increased bone loss seen with aging.
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