Vascular calcification--a passive process in need of inhibitors.
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[The usefulness of biochemical markers of bone remodelling in the diagnosis and follow-up of Paget's disease of bone, primary hyperparathyroidism, tumoral hypercalcemia and postmenopausal osteoporosis. I. The markers of bone formation].
Rapid detection of the exact changes in bone remodelling is exceptionally important. In this paper, the latest bone remodelling biochemical markers are reviewed. Some of them have already been used for a long time, and their utility has been widely demonstrated. The newest ones, in experimental stage, can be used as a complement to the others. The bone remodelling markers reviewed are: 1) Alkaline phosphatase; 2) osteocalcin; 3) Other noncollagen of bone matrix such as osteonectin, GLA-protein of the matrix, osteopontine and alpha 2-HS-glycoprotein; 4) Procollagenous and other collagenous peptides of the matrix (C terminal of type-I procollagen and urinary elimination of nondialysis hydroxyproline. Amongst the bone resorption markers studied are: 1) Calcium/creatinine urinary quotient; 2) Tartrate resistant acid phosphatase; 3) Urinary hydroxyproline; 4) Other substances derived from collagen disruption such as hydroxilysin glycoside, piridinolinic intermolecular bridges and the enzymatic activity of proline iminopeptidase. We endeavoured to collect all the most important references on the matter, especially those relating to Paget's disease of the bone, primary hyperparathyroidism, tumoral hypercalcemia and postmenopausal osteoporosis.
Biomarkers↗
[Usefulness of bone remodelling biochemical markers in the diagnosis and follow-up of Paget's bone disease, primary hyperparathyroidism, tumor hypercalcemia, and postmenopausal osteoporosis. II. Bone resorption markers].
Rapid detection of the exact changes in bone remodelling is exceptionally important. In this paper, the latest bone remodelling biochemical markers are reviewed. Some of them have already been used for a long time, and their utility has been widely demonstrated. The newest ones, in experimental stage, can be used as a complement to the others. The bone remodelling markers reviewed are: 1) Alkaline phosphatase; 2) osteocalcin; 3) other noncollagen of bone matrix such as osteonectin, GLA-protein of the matrix, osteopontine and alpha 2-HS-glycoprotein; 4) Procollagenous and other collagenous peptides of the matrix (C terminal of type I procollagen and urinary elimination of non-dialysis hydroxyproline. Amongst the bone resorption markers studied are: 1) Calcium/creatinine urinary quotient; 2) Tartrate resistant acid phosphatase; 3) Urinary hydroxyproline; 4) Other substance derived from collagen disruption such as hydroxylysine glycoside, piridinolinic intermolecular bridges and the enzymatic activity of proline iminopeptidase. We endeavored to collect all the most important references on the matter, especially those relating to Paget's disease of the bone, primary hyperparathyroidism, tumoral hypercalcemia and postmenopausal osteoporosis.
Acid Phosphatase↗
High prevalence of vitamin D deficiency and reduced bone mass in elderly women with Alzheimer's disease.
Patients with Alzheimer's disease (AD) are at increased risk for falls and hip fractures. To better understand causes and prevention, we measured bone mineral density (BMD) in the second metacarpals of 46 ambulatory elderly women with AD and analyzed its relation to serum biochemical indices, sunlight exposure, and vitamin D intake. BMD was significantly less than in age-matched controls. In 26% of AD patients, the serum 25-hydroxyvitamin D (25-OHD) concentration was at a deficient level (5-10 ng/mL), and in 54% it was at an osteomalacic level (<5 ng/mL). Concentrations of ionized calcium were significantly lower in patients. Conversely, concentrations of serum bone Gla-protein and urinary hydroxyproline in patients were significantly higher than in controls. BMD correlated positively with 25-OHD concentration (p = 0.0041) and negatively with parathyroid hormone (PTH) concentration (p = 0.0022). PTH was higher in patients than in controls, and correlated negatively with 25-OHD (p < 0.0001). Many AD patients were sunlight-deprived and consumed less than 100 IU of vitamin D per day. We concluded that vitamin D deficiency due to sunlight deprivation and malnutrition, together with compensatory hyperparathyroidism, contributes significantly to reduced BMD in AD patients. Low BMD increases risk of hip fractures in patients with AD, but may be improved by vitamin D supplementation.
Aged↗
Molecular determinants of arterial calcification.
Calcification of extracellular matrix (ECM) can be either physiological or pathological. Physiological calcification (or mineralization) of ECM is restricted to bones, teeth and, to a lesser extent, growth plate cartilages. Pathological calcification appears often in the ECM of arteries where it is a frequent complication of atherosclerosis. However, calcification of the ECM of arteries is not restricted to atherosclerosis. Indeed, human diseases have been described that are characterized by calcification of the aortic media in the absence of any atherosclerotic lesions. The existence of these rare diseases, along with several mouse models recently generated and discussed below, indicates that the formation of atherosclerotic lesions and the calcification of the artery ECM are controlled by different genetic pathways. This emerging knowledge has implications for our understanding of ECM calcification beyond atherosclerosis.
Animals↗
Vitamin K nutrition and osteoporosis.
Although the abundance of vitamin K-dependent proteins in bone suggests an important function, the precise role of vitamin K in skeletal health remains to be determined. Serum concentrations of vitamin K are reportedly reduced in older individuals and persons with osteoporotic fracture. Whether this is causally related to vitamin K insufficiency or simply reflects inadequate nutritional status is unclear. Circulating levels of undercarboxylated osteocalcin may be a sensitive marker of vitamin K inadequacy and have been reported to be increased in both postmenopausal women and individuals who sustained hip fracture. It is also possible that vitamin K indirectly affects the skeleton via control of renal calcium excretion. The effect of vitamin K antagonists (oral anticoagulants) on both renal calcium excretion and bone density is controversial. Thus, many of the reports implicating a role for vitamin K insufficiency in the development of osteoporosis are conflicting. This review summarizes current knowledge regarding a possible role of vitamin K insufficiency in the pathogenesis of osteoporosis.
Aged↗
Matrix gamma-carboxyglutamic acid protein (MGP) G-7A and T-138C gene polymorphisms in Indian (Mayo and Teenek) and Mestizo populations from Mexico.
Matrix gamma-carboxyglutamic acid protein (MGP) genotypes (G-7A and T-138C) were determined in 266 individuals from three Mexican populations. Mexicans showed increased frequencies of the G-7A G allele and the G7-A GG genotype compared to Europeans. For the T-138C genotype, we found differences among the Mexicans. This study could help to define the significance of MGP polymorphisms as genetic markers in Amerindian populations.
Calcium-Binding Proteins↗
The vitamin D-responsive element in the rat bone Gla protein gene is an imperfect direct repeat that cooperates with other cis-elements in 1,25-dihydroxyvitamin D3- mediated transcriptional activation.
The gene for rat bone gla protein (BGP) was isolated and 1250 basepairs (bp), including 1100 bp of 5' flanking DNA, were placed up-stream of the human GH reporter gene. After transient transfection into the osteoblast-like rat osteosarcoma cell line ROS 17/2.8, the BGP promoter demonstrated a low level of basal activity that was increased approximately 10-fold by the addition of 10(-8) M 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. A single 250-bp fragment (-523 to -274) was sufficient to confer hormone inducibility upon both heterologous and homologous promoters. Deletion studies, complemented by evaluation with synthetic oligomers, enabled localization of the 1,25-(OH)2D3 response element to within 19 bp (-456 to -438), containing an element with an imperfect direct repeat [GGTGA(N4)GGACA] and homology to other steroid-responsive elements. Gel retardation assays demonstrated that partially purified chick intestinal 1,25-(OH)2D3 receptor bound specifically and with high affinity to a DNA fragment containing the putative 1,25-(OH)2D3 response element, and this binding was perturbed by monoclonal antibodies to the 1,25-(OH)2D3 receptor. Surprisingly, the 250-bp fragment, when linked in an antisense orientation with respect to the BGP promoter, blocked basal and hormone-dependent gene expression. However, a 246-bp fragment 5' to the 250-bp element (-1100 to -855) restored 20-fold inducibility when linked to the first fragment in the same orientation, suggesting cooperativity between at least two elements to achieve the hormonal regulation observed in this gene.
Animals↗
Expression of mRNA for matrix gamma-carboxyglutamic acid protein during progression of atherosclerosis in aortae of Watanabe heritable hyperlipidemic rabbits.
In an effort to characterize mRNAs that are highly expressed during atherosclerosis, we employed differential hybridization screening of a cDNA library constructed from total RNA derived from the aorta of Watanabe heritable hyperlipidemic (WHHL) rabbits. Characterizing the cDNAs for mRNAs that are present in large amounts in WHHL rabbit aortae, we identified a positive clone encoding matrix gamma-carboxyglutamic acid protein (MGP). The primary structure of rabbit MGP was deduced from nucleotide sequence analysis of the cDNA. Northern blot analysis of total RNA prepared from aortae of WHHL and normal rabbits of various ages indicated that the expression of MGP mRNA increased in proportion to the progression of atherosclerosis in WHHL rabbits. Analysis of MGP mRNA by in situ hybridization revealed that a significant amount of MGP mRNA is accumulated in atherosclerotic lesions of WHHL rabbits, suggesting that the expression of MGP mRNA is correlated with the progression of atherosclerosis.
Amino Acid Sequence↗
Force-induced rapid changes in cell fate at midpalatal suture cartilage of growing rats.
The application of expansional force induces replacement of the cartilaginous tissue with bone at the midpalatal suture of growing rats. We examined the early cellular events evoked by force by analyzing the expression of proliferating cell nuclear antigen (PCNA), an operational marker of cell proliferation, and of several bone matrix proteins. A rectangular orthodontic appliance was set between the right and left upper molars of four-week-old rats, with 50 g of initial expansional force. Two days after application of the force, the pre-existing cartilage was separated laterally. Mesenchymal cells with stretched shapes were arranged parallel to the expansional force and filled the center of the suture. Only a few of these stretched cells exhibited nuclear accumulation of PCNA. In contrast, many polygonal mesenchymal cells distributed along the inner lateral side of the cartilaginous tissue exhibited strong immunoreactivity for PCNA. Localization of alkaline phosphatase activity overlapped into this proliferating cell zone. Nascent extracellular matrix under the proliferating cells was positive for osteocalcin, indicating commencement of active bone formation. These findings indicated that, among mesenchymal cells subjected to expansional forces, only cells located on the inner side of the cartilaginous tissue proliferate and differentiate into osteoblasts. In agreement with rapid bone growth progression, apoptosis was also observed in the zone of proliferating cells, as measured by TdT-mediated dUTP-biotin nick end labeling (TUNEL) assays.
Animals↗
[Atherosclerosis and vascular calcification in hemodialysis patients].
Cardiovascular disease is the largest cause of mortality in hemodialysis patients. Cardiovascular mortality is fivefold to twentyfold higher in hemodialysis patients than in the general population. Atherosclerosis and vascular calcification are the characteristic complications in hemodialysis patients. Hemodialysis patients have traditional risk factors such as abnormal lipid metabolism and uremia-related risk factors such as oxidative stress and hyperphosphatemia. Oxidative stress takes place by increased production of oxidants by leukocytes and antioxidant loss of vitamin C and E. Oxidatively modified LDL exist in the circulation by excess of oxidative stress in hemodialysis patients. Oxidative stress is a major contributor to accelerated development atherosclerosis. Oxidative stress and hyperphosphatemia also influence vascular calcification. The pattern of vascular calcification in hemodialysis patient is characterized by mineral deposition in the tunica media. It is reported that the obvious calcification in aorta and artery of the MGP knockout mouse is recognized. It is indicated that MGP has the inhibitory effect of the calcification of vessel wall. Vitamin E protects atherosclerosis and vascular calcification in hemodialysis patients. It is also important to control hyperphosphatemia for vascular calcification.
Animals↗
Possible relation of osteopontin to development of psammoma bodies in human papillary thyroid cancer.
BACKGROUND: Psammoma bodies are often observed in papillary carcinomas of the thyroid. Recently we reported that osteopontin (OPN) appears to play an important role in the development of psammoma bodies in meningiomas. Because the morphology and components of psammoma bodies in papillary carcinoma of the thyroid are similar to those of psammoma bodies in meningioma, we examined whether OPN was related to the psammoma bodies in papillary carcinoma of the thyroid. METHODS: Expression of OPN mRNA was examined by Northern blotting and in situ hybridization. Immunohistochemistry was performed to localize the deposition of OPN protein and to identify the type of OPN mRNA-expressing cells. RESULTS: The expression of OPN mRNA was detected in papillary thyroid carcinomas but not in normal thyroid tissue. Osteopontin mRNA-expressing cells were present around the psammoma bodies, and the localization of OPN protein was consistent with that of psammoma bodies. The OPN mRNA-expressing cells were identified as CD68-positive macrophages. CONCLUSION: Osteopontin produced by macrophages may play a significant role in the development of psammoma bodies in papillary carcinoma of the thyroid.
Blotting, Northern↗
Gene expression in osteoblastic cells.
Osteoblasts, the bone-forming cells, synthesize the macromolecules of the bone matrix including: type I collagen; osteocalcin; osteonectin; osteopontin; proteoglycan I and II; bone sialoprotein; matrix gla-protein; bone glycoprotein 75; several other proteins, which have not been extensively characterized; growth factors, including transforming growth factor beta and fibroblast growth factor. Osteoblasts also have high levels of the membrane-bound enzyme, alkaline phosphatase, which plays a role in matrix mineralization, and receptors for tissue-specific hormones, such as parathyroid hormone, as well as many other hormones, cytokines and growth factors, which regulate bone growth, differentiation and metabolism. The expression of these various proteins, most of which are not unique to bone but which together characterize the bone phenotype, is induced during osteoblastic differentiation in a stepwise fashion, suggestive of multiple regulatory factors. The detailed sequence of the expression of osteoblastic genes in situ has not been fully characterized. It appears that type I collagen and alkaline phosphatase are expressed early during the commitment to the osteoblastic phenotype, whereas osteopontin and osteocalcin appear late during osteoblastic differentiation. Diversity among "osteoblastic" cells is also apparent, probably not all osteoblastic cells express all the features. A large number of osteoblastic models are currently available to study the expression of osteoblast-related genes in vitro. These include primary cultures from calvaria or trabecular bone from several species, including humans, osteosarcoma-derived cell lines, and experimentally immortalized cells. Some of these in vitro models, especially the calvaria-derived cultures, undergo changes which mimic osteoblastic differentiation in vivo. The study of these and other cell models started providing insights into the regulation of gene expression in osteoblastic cells. In addition to a vast body of information on the conditions required for the expression of various proteins in culture and their regulation by hormones and growth factors, more detailed information on specific genes has recently been obtained. For example, regulation of type I collagen gene expression has been studied in osteosarcoma cell lines where 1,25(OH)2 vitamin D3 was shown to act via specific DNA segment(s) in the 5' flanking region of the gene, while parathyroid hormone affected gene expression by altering the stability of the transcripts. TGF beta 1, which stimulates osteogenesis, was shown to promote the transcription of osteopontin and type I collagen, the latter effect requiring the binding site for the transactivating protein, nuclear factor I.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Vascular calcification: mechanisms and clinical ramifications.
Vascular calcification, long thought to result from passive degeneration, involves a complex, regulated process of biomineralization resembling osteogenesis. Evidence indicates that proteins controlling bone mineralization are also involved in the regulation of vascular calcification. Artery wall cells grown in culture are induced to become osteogenic by inflammatory and atherogenic stimuli. Furthermore, osteoclast-like cells are found in calcified atherosclerotic plaques, and active resorption of ectopic vascular calcification has been demonstrated. In general, soft tissue calcification arises in areas of chronic inflammation, possibly functioning as a barrier limiting the spread of the inflammatory stimulus. Atherosclerotic calcification may be one example of this process, in which oxidized lipids are the inflammatory stimulus. Calcification is widely used as a clinical indicator of atherosclerosis. It progresses nonlinearly with time, following a sigmoid-shaped curve. The relationship between calcification and clinical events likely relates to mechanical instability introduced by calcified plaque at its interface with softer, noncalcified plaque. In general, as calcification proceeds, interface surface area increases initially, but eventually decreases as plaques coalesce. This phenomenon may account for reports of less calcification in unstable plaque. Vascular calcification is exacerbated in certain clinical entities, including diabetes, menopause, and osteoporosis. Mechanisms linking them must be considered in clinical decisions. For example, treatments for osteoporosis may have unanticipated effects on vascular calcification; the converse also applies. Further understanding of processes governing vascular calcification may yield new therapeutic options for vascular disease.
Animals↗
Mechanisms of vascular calcification.
Vascular calcification is highly prevalent and correlated with high rates of cardiovascular mortality in chronic kidney disease patients. Recent evidence suggests that mineral, hormonal, and metabolic imbalances that promote phenotype change in vascular cells as well as deficiencies in specific mineralization inhibitory pathways may be important contributory factors for vascular calcification in these patients. This article reviews current mechanisms proposed for the regulation of vascular calcification and data supporting their potential contribution to this process in chronic kidney disease.
Animals↗
Interaction of vascular and bone disease in patients with normal renal function and patients undergoing dialysis.
The cardiovascular risk of patients undergoing dialysis is 20-30 times higher than that of individuals of the same age, without abnormal renal function, from the general population. Observational studies of patients with normal and abnormal renal function have shown that there is an association between bone disease, vascular calcification and cardiovascular outcome and that worsening of these conditions happens in parallel. Basic science studies are elucidating several mechanisms that could explain the interaction between bone disease, vascular calcification and cardiovascular outcome. For example, the expression of osteoprotegerin-a protein that regulates bone resorption by binding receptor activator of nuclear factor kappaB (RANK) ligand (RANKL), thus preventing interaction with the receptor RANK and the stimulation of osteoclast maturation-is regulated by several cytokines. Additionally, osteoprotegerin seems involved in the genesis of atherosclerosis. Imbalances of bone mineral metabolism, bone matrix secretion and vascular smooth-muscle-cell apoptosis seem involved in the ossification of the arterial wall in chronic kidney disease, and could explain some of the complex interactions between bone and vascular disease in renal failure. In this article we present a brief review of some of the basic mechanisms involved in vascular calcification and the clinical evidence of an association of vascular and bone disease.
Aged↗
Prenatal diagnosis and investigation of a fetus with chondrodysplasia punctata, ichthyosis, and Kallmann syndrome due to an Xp deletion.
We report the prenatal diagnosis of a male fetus with X-linked recessive chondrodysplasia punctata (CDPX), steroid sulphatase (STS) deficiency, X-linked Kallmann syndrome (KAL), and a chromosome deletion at Xp22.31. Biochemical analysis of bone from this case indicates that CDPX is not a defect of vitamin K metabolism. Immunocytochemical study of the brain suggests that KAL is a defect in neuronal migration.
Adult↗
Genetic determinants of arterial calcification associated with atherosclerosis.
Increasing research interest has focused on arterial calcification in the setting of atherosclerosis. Many features of atherosclerosis-related calcification provide useful clinical information. For example, calcium mineral deposits frequently form in atherosclerotic plaque, and intimal arterial calcification can be used as a surrogate marker for atherosclerosis; also, calcium deposits are readily and noninvasively quantified, which is useful because greater amounts of coronary calcification predict a higher risk of myocardial infarction and death. Several mechanisms leading to calcification associated with atherosclerosis have been proposed; however, no direct testing of proposed mechanisms has yet been reported. Studies in genetically altered animals and in humans have shed light on potential genetic determinants, which in turn could form the basis for a more comprehensive understanding of the factors affecting calcification within plaque and the associated pathobiologic implications. We review proposed molecular and cellular mechanisms of atherosclerosis-associated arterial calcification, summarize genetic influences, and suggest areas in which further investigation is needed. Understanding the molecular and genetic determinants of specific structural plaque components such as calcification can provide a solid foundation for the development of novel therapeutic approaches to favorably alter plaque structure and minimize vulnerability to arterial rupture.
Animals↗