Abnormal calcium metabolism in normocalcaemic sarcoidosis.
In studies of calcium metabolism in 13 unselected patients with untreated sarcoidosis all were normocalcaemic but five had hypercalcuria. All had normal renal function. Calcium absorption was indexed by a double isotope test. 45Ca hyperabsorption occurred in six patients. Ten kinetic studies were carried out with 47Ca and in six bone turnover was increased. 45Ca absorption correlated well with the calculated bone uptake rate of calcium, and with urine calcium excretion. These results suggest that in sarcoidosis abnormalities in calcium metabolism are fairly common although they rarely result in sustained hypercalcaemia. (+info)
A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo.
Morphogenesis depends on the precise control of basic cellular processes such as cell proliferation and differentiation. Wnt5a may regulate these processes since it is expressed in a gradient at the caudal end of the growing embryo during gastrulation, and later in the distal-most aspect of several structures that extend from the body. A loss-of-function mutation of Wnt5a leads to an inability to extend the A-P axis due to a progressive reduction in the size of caudal structures. In the limbs, truncation of the proximal skeleton and absence of distal digits correlates with reduced proliferation of putative progenitor cells within the progress zone. However, expression of progress zone markers, and several genes implicated in distal outgrowth and patterning including Distalless, Hoxd and Fgf family members was not altered. Taken together with the outgrowth defects observed in the developing face, ears and genitals, our data indicates that Wnt5a regulates a pathway common to many structures whose development requires extension from the primary body axis. The reduced number of proliferating cells in both the progress zone and the primitive streak mesoderm suggests that one function of Wnt5a is to regulate the proliferation of progenitor cells. (+info)
Mechanisms of GDF-5 action during skeletal development.
Mutations in GDF-5, a member of the TGF-beta superfamily, result in the autosomal recessive syndromes brachypod (bp) in mice and Hunter-Thompson and Grebe-type chondrodysplasias in humans. These syndromes are all characterised by the shortening of the appendicular skeleton and loss or abnormal development of some joints. To investigate how GDF-5 controls skeletogenesis, we overexpressed GDF-5 during chick limb development using the retrovirus, RCASBP. This resulted in up to a 37.5% increase in length of the skeletal elements, which was predominantly due to an increase in the number of chondrocytes. By injecting virus at different stages of development, we show that GDF-5 can increase both the size of the early cartilage condensation and the later developing skeletal element. Using in vitro micromass cultures as a model system to study the early steps of chondrogenesis, we show that GDF-5 increases chondrogenesis in a dose-dependent manner. We did not detect changes in proliferation. However, cell suspension cultures showed that GDF-5 might act at these stages by increasing cell adhesion, a critical determinant of early chondrogenesis. In contrast, pulse labelling experiments of GDF-5-infected limbs showed that at later stages of skeletal development GDF-5 can increase proliferation of chondrocytes. Thus, here we show two mechanisms of how GDF-5 may control different stages of skeletogenesis. Finally, our data show that levels of GDF-5 expression/activity are important in controlling the size of skeletal elements and provides a possible explanation for the variation in the severity of skeletal defects resulting from mutations in GDF-5. (+info)
Elevated carboxy terminal cross linked telopeptide of type I collagen in alcoholic cirrhosis: relation to liver and kidney function and bone metabolism.
BACKGROUND: The carboxy terminal cross linked telopeptide of type I collagen (ICTP) has been put forward as a marker of bone resorption. Patients with alcoholic liver disease may have osteodystrophy. AIMS: To assess circulating and regional concentrations of ICTP in relation to liver dysfunction, bone metabolism, and fibrosis. METHODS: In 15 patients with alcoholic cirrhosis and 20 controls, hepatic venous, renal venous, and femoral arterial concentrations of ICTP, and bone mass and metabolism were measured. RESULTS: Circulating ICTP was higher in patients with cirrhosis than in controls. No overall significant hepatic disposal or production was found in the patient or control groups but slightly increased production was found in a subset of patients with advanced disease. Significant renal extraction was observed in the controls, whereas only a borderline significant extraction was observed in the patients. Measurements of bone mass and metabolism indicated only a mild degree of osteodystrophy in the patients with cirrhosis. ICTP correlated significantly in the cirrhotic patients with hepatic and renal dysfunction and fibrosis, but not with measurements of bone mass or metabolism. CONCLUSIONS: ICTP is highly elevated in patients with cirrhosis, with no detectable hepatic net production or disposal. No relation between ICTP and markers of bone metabolism was identified, but there was a relation to indicators of liver dysfunction and fibrosis. As the cirrhotic patients conceivably only had mild osteopenia, the elevated ICTP in cirrhosis may therefore primarily reflect liver failure and hepatic fibrosis. (+info)
Predicting bone loss following orthotopic liver transplantation.
BACKGROUND: Hepatic osteodystrophy occurs in the majority of patients with advanced chronic liver disease with the abnormalities in bone metabolism accelerating following orthotopic liver transplantation (OLT). AIMS: To examine changes in bone mineral density (BMD) following OLT and to investigate factors that lead to bone loss. METHODS: Twelve patients had BMD (at both the lumbar spine (LS) and femoral neck (FN)) and biochemical markers measured preoperatively and for 24 months following OLT. RESULTS: BMD was low in 75% of patients prior to OLT and decreased significantly from baseline at the LS at three months and the FN at six months. BMD began to increase thereafter at both sites, approaching baseline values at the LS by 12 months. Bone formation markers, osteocalcin and procollagen type I carboxy propeptide, decreased immediately post-OLT, with a concomitant increase seen in the resorption markers pyridinoline and deoxypyridinoline. This resulted in a negative uncoupling index early post-OLT, that rebounded to positive values after six months. There was a significant correlation between the change in the uncoupling index between six and three months which preceded the increase in BMD at 12 months. The decrease in BMD recorded early post-OLT correlated with vitamin D levels at three months. CONCLUSIONS: Results suggest that increased resorption and inadequate formation are the major contributors to additional bone loss following OLT. Non-invasive biochemical markers precede later changes in BMD in this patient group following OLT and may have a role in investigating and planning intervention strategies to prevent bone loss in future studies. (+info)
The use of variable lactate/malic dehydrogenase ratios to distinguish between progenitor cells of cartilage and bone in the embryonic chick.
The activities of LDH and MDH have been studied, both in differentiated cartilage and bone from the embryonic chick, and in the pool of mixed osteogenic and chondrogenic stem cells found on the quadratojugal, a membrane bone. In confirmation of the model proposed by Reddi & Huggins (1971) we found that the LDH/MDH ratio was greater than 1 in cartilage and less than 1 in bone. Furthermore we established, for the first time, that ratios occurred in the chondrogenic and osteogenic stem cells, similar to the ratios in their differentiated counterparts. Alteration in LDH/MDH resulted from variations in the level of LDH/mug protein. MDH/mug protein remained constant, even when LDH/MDH was changing. We interpret these results in terms of adaptation of chondrogenic progenitor cells for anaerobic metabolism and anticipate that our model will be applicable to other skeletal systems where stem cells are being studied. (+info)
Effect of shellfish calcium on the apparent absorption of calcium and bone metabolism in ovariectomized rats.
Fossil shellfish powder (FS) and Ezo giant scallop shell powder (EG) were rendered soluble with lactate and citrate under decompression (FSEx and EGEx, respectively) and we examined the effects of lactate-citrate solubilization of FS and EG on mineral absorption, tissue mineral contents, serum biochemical indices and bone mineral density (BMD) in ovariectomized (OVX) rats. The apparent absorption ratios of minerals tended to be high in the rats fed with the solubilized mineral sources, those in the FSEx group being significantly higher than in the FS group. There was no significant difference in the tibia mineral content among the OVX groups. BMD at the distal femoral diaphysis was significantly increased by FSEx and EGEx feeding. It is suggested that solubilization with lactate and citrate under decompression increased the solubility and bioavailability of calcium from such natural sources of shellfish calcium as FS and EG. (+info)
A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene.
We have identified a novel fibroblast growth factor receptor 3 (FGFR3) missense mutation in four unrelated individuals with skeletal dysplasia that approaches the severity observed in thanatophoric dysplasia type I (TD1). However, three of the four individuals developed extensive areas of acanthosis nigricans beginning in early childhood, suffer from severe neurological impairments, and have survived past infancy without prolonged life-support measures. The FGFR3 mutation (A1949T: Lys650Met) occurs at the nucleotide adjacent to the TD type II (TD2) mutation (A1948G: Lys650Glu) and results in a different amino acid substitution at a highly conserved codon in the kinase domain activation loop. Transient transfection studies with FGFR3 mutant constructs show that the Lys650Met mutation causes a dramatic increase in constitutive receptor kinase activity, approximately three times greater than that observed with the Lys650Glu mutation. We refer to the phenotype caused by the Lys650Met mutation as "severe achondroplasia with developmental delay and acanthosis nigricans" (SADDAN) because it differs significantly from the phenotypes of other known FGFR3 mutations. (+info)