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Biomedical subjects

J B Kopp

Publications and source records attributed to J B Kopp.

At least 73 records · Page 4Linked to original sources
PubMed1991

Osteogenesis imperfecta: changes in noncollagenous proteins in bone.

The noncollagenous proteins osteonectin, bone sialoprotein, osteocalcin, the small proteoglycan decorin (PG II), and alpha 2-HS glycoprotein (which is synthesized in the liver but highly concentrated in bone) were measured in extracts of cortical bone from 3 type I, 2 type II, 8 type III and 13 type IV patients with osteogenesis imperfecta (OI) and from 7 control subjects. Osteonectin was found to be reduced in the bone of all OI patients. The bone from severely affected type III OI patients contained the lowest levels of osteonectin. In contrast, bone sialoprotein was found to be elevated in the bones of OI patients. The highest levels were found in individuals classified as type IV patients. Osteocalcin and alpha 2-HS glycoprotein concentrations were increased in all OI patients. Decorin levels were not significantly altered in OI bones compared to controls. These changes in the concentrations of the noncollagenous proteins may contribute to the fragility of the OI bone by interfering with complete mineralization and/or normal tissue architecture.

Adolescent↗
PubMed1991

Changes in apatite crystal size in bones of patients with osteogenesis imperfecta.

Apatite crystal size in compact bone of children (age less than 11 years) and adolescents (age greater than 12 years) with osteogenesis imperfecta (OI) was analyzed by X-ray diffraction. Eight type I, 4 type II, 11 type III, and 14 type IV OI patients were studied along with 9 controls. The crystal size was most significantly reduced in type II patients, all of whom had died at birth. Crystal size was also diminished in both children and adolescents with types III and IV, whereas with type I OI, crystal size was reduced in children only, returning to normal in adolescence. There was a trend toward increased bone crystal size with age in both OI patients and controls.

Adolescent↗
PubMed1991

Angiotensin II receptor-mediated proliferation of cultured human fetal mesangial cells.

Accumulating evidence suggests that angiotensin II (Ang II) may play an important role in renal growth and glomerular development. During nephrogenesis, a complex relationship between the capillary and renal mesangium develops. Since the mesangial cell is a centrally-located pericyte with contractile, endocrine, and immune modulating functions, it may play a unique role in maintaining normal glomerular function. Therefore, we examined whether Ang II affects proliferation of human fetal mesangial cells in vitro and compared these findings to mesangial cells isolated from adult kidney. In these primary isolates, we studied the relationship between Ang II receptors and the mitogenic activity of angiotensin. Scatchard analysis of the binding of 125I[Sar1,Ile8]Ang II to subconfluent cultured human fetal mesangial cells revealed the presence of one class of binding sites with a Kd of 1.25 nM and a Bmax of 70 fmol/1 x 10(5) cells. Ang II receptors on adult mesangial cells had similar binding kinetics with a Kd of 1.6 nM and Bmax of 65 fmol/10(5) cells in subconfluent culture. In subconfluent culture of fetal mesangial cells, Ang II increased [3H]thymidine incorporation by 130% (P less than 0.005). In subconfluent culture of adult mesangial cells, Ang II increased [3H]thymidine incorporation by only 35% (P less than 0.05). In confluent culture of fetal mesangial cells, Ang II receptor number and mitogenic response were reduced. The Ang II antagonist [Sar1,Ile8]Ang II (1 microM) inhibited the mitogenic response of fetal mesangial cells to Ang II. Ang II increased fetal mesangial cell number by 25% (after 4 days) in serum-free medium supplemented with insulin or supplemented with insulin and 1% Nutridoma (P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Adult and fetal human mesangial cells interact with specific laminin domains.

Mesangial cells are centrally located pericytes in the renal glomerulus. They are surrounded by an extracellular matrix and directly contact the glomerular basement membrane in vivo. Because these interactions are critical for renal development and function, we have studied human mesangial cell interactions with laminin, a major adhesive component of basement membranes present in the extracellular matrix of the mesangium. Human fetal and adult mesangial cell attachment was stimulated by both laminin and the laminin-derived synthetic peptides YIGSR-NH2, CQAGTFALRGDNPQG-NH2, and CIKVAVS-NH2. Furthermore, mesangial cells spread on laminin as well as on both the RGD-containing and CIKVAVS peptides. When added in solution, all three peptides inhibited mesangial cell attachment to laminin, and the latter two peptides inhibited mesangial cell spreading on laminin. Laminin affinity column chromatography demonstrated several low-molecular-mass laminin-binding proteins ranging from between 35 and 42 kDa, which predominated in fetal mesangial cells, whereas a higher molecular mass laminin-binding protein of 65 kDa was predominant in adult mesangial cells. Western blot analysis with an anti-32-kDa laminin-binding protein antibody showed increased expression of both 31- and 42-kDa proteins in fetal mesangial cells when compared with the adult. The antisera to the 32-kDa laminin-binding protein also inhibited fetal mesangial spreading on the CIKVAVS peptide. Western blot analysis with an anti-67-kDa laminin-binding protein antibody revealed a 110-kDa protein in adult mesangial cells that was not present in fetal mesangial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Water deprivation stimulates transforming growth factor-beta 2 accumulation in the juxtaglomerular apparatus of mouse kidney.

Transforming growth factor-beta (TGF-beta) modulates the growth and differentiation of many cells and often functions in an autocrine or paracrine fashion. The myoepithelial cells of the renal juxtaglomerular apparatus (JGA) synthesize and secrete renin. Under conditions which chronically stimulate renin production, the JGA undergoes hypertrophy and hyperplasia. The molecular factors responsible for these changes in the JGA have not been identified. In the present study, plasma renin activity was stimulated in the mouse by water deprivation. Using immunoperoxidase staining with specific antibodies against TGF-beta 1, beta 2, and beta 3, we found increased TGF-beta 2 accumulation in the JGA and interlobular arteries. Immunostaining with renin antiserum demonstrated colocalization of TGF-beta 2 and renin. TGF-beta 1 and beta 3 expression was not different between control and water-deprived mice. Our results suggest that in the setting of water deprivation, TGF-beta 2 is localized in a manner which would allow it to act either as a growth factor for or as a phenotypic modulator of the JGA and renal arterioles.

Angiotensin II↗
PubMed1991

Invasive activity, spreading on and chemotactic response to laminin are properties of high but not low metastatic mouse osteosarcoma cells.

We have examined the interactions of low (Os43 and OS48) and high (Os50/K8 and Os50/K12) metastatic cell lines derived from osteosarcomas (Os) of the Balb/c mouse with fibronectin (FN) and laminin (LN). All of these cell lines formed osteogenic tumors when transplanted subcutaneously into syngeneic mice. Os43 and Os48 cells gave rise to few metastases while the Os50/K8 and Os50/K12 cells were highly metastatic. In an in vitro chemoinvasion assay only the highly metastatic cells were able to invade a reconstituted basement membrane. Although the interactions of all cell lines with FN were quite similar, their response to LN differed considerably. Within each of the cell lines, chemotactic response to and cell spreading on LN were closely correlated. Highly metastatic Os cells migrated to and spread on LN substrates to a much greater extent than low metastatic cells. Os43 and particularly Os48 showed very much low migration to LN, similar to that of Balb/c 3T3 fibroblasts. They also spread poorly on LN, resembling the behavior of normal human bone cells which were used as a control. Thus, with these assays it is possible to distinguish the LN interactions associated with the metastatic phenotype of Os cells. The acquisition of LN recognition in tumor cells of bone origin may be related to their ability to invade and metastasize. This system may be valuable for the study of LN recognition molecules, their appearance, or changes with the metastatic phenotype.

Animals↗
PubMed1990

Sodium fluoride lacks mitogenic activity for fetal human bone cells in vitro.

Sodium fluoride has been shown to be effective therapy for some patients with vertebral osteoporosis. Data from histomorphometric studies in patients and animals suggest that at least part of this effect may be a consequence of a proliferative effect of fluoride, either direct or indirect, on the osteoblast or on an osteoblastic precursor cell. Experiments with osteoblastic cells derived from embryonic chick calvaria have demonstrated a mitogenic effect of fluoride. The present study examined whether fluoride affects in a similar way fetal human bone cells derived from femur or calvaria. Under a variety of culture conditions, including medium supplemented with serum and in serum-free medium, fluoride did not alter the proliferative rate of human bone cells as measured by thymidine incorporation and direct cell counting.

Bone and Bones↗
PubMed1990

Sodium fluoride does not increase human bone cell proliferation or protein synthesis in vitro.

The efficacy of sodium fluoride therapy for osteoporosis remains controversial. Evidence from clinical studies and from animals receiving fluoride has suggested that fluoride might act on bone to increase osteoblast numbers and matrix synthesis. In order to examine the hypothesis that fluoride has a direct mitogenic or anabolic action on the osteoblast, we tested the effect of fluoride on first passage human osteoblastic bone cells grown from collagenase-treated trabecular bone fragments. Under a variety of culture conditions, including both medium supplementation with serum and with a chemically defined medium, fluoride in doses ranging from 10(-6) to 10(-3) M did not alter cell proliferation as measured either by thymidine incorporation or by direct cell counting. Furthermore, exposure to fluoride under conditions of low serum supplementation did not alter either the total protein synthesis of the cells or their biosynthetic profile. These data suggest that fluoride does not act in vitro upon differentiated osteoblastic bone cells derived from adult human patients.

Aged↗
PubMed1990

Cellular and molecular mechanisms of cyclosporin nephrotoxicity.

Cyclosporin therapy is associated with several forms of nephrotoxicity, the most significant of which are reversible impairment of glomerular filtration and irreversible interstitial fibrosis. Impaired glomerular filtration is due to both reduction in Kf, the glomerular capillary ultrafiltration coefficient, and to reduction in renal blood flow. The mechanisms responsible for the low Kf are not well defined, but heightened mesangial cell contractility may contribute. Reduced renal blood flow with chronic cyclosporin therapy arises from both endothelial damage and altered eicosanoid metabolism, in particular increased thromboxane synthesis. Renal interstitial fibrosis, which develops in some patients after approximately 6-12 months of cyclosporin therapy, poses a major limitation to the chronic use of the drug. Two mechanisms likely contribute to cyclosporin-associated interstitial fibrosis. First, endothelial injury and vasoconstriction produce renal ischemia, which in turn is associated with enhanced synthesis of extracellular matrix proteins. Second, cyclosporin likely influences the accumulation of matrix proteins in the renal interstitium through nonhemodynamic mechanisms, as suggested by altered matrix accumulation in non-renal tissues. This effect of cyclosporin may be direct or indirect, via mediators including cytokines, peptide growth factors, and thromboxane. The molecular mechanisms of cyclosporin action on immunologic and mesenchymal cells are active areas of investigation. Intracellular targets of cyclosporin include mitochondrial respiration, cellular calcium signaling, protein kinase C, protein synthesis, and peptidyl-prolyl isomerases. However, the significance of these intracellular effects for cyclosporin nephrotoxicity remains to be demonstrated.

Amino Acid Isomerases↗
PubMed1989

Osteonectin promoter. DNA sequence analysis and S1 endonuclease site potentially associated with transcriptional control in bone cells.

To understand the basis of osteonectin (SPARC) transcriptional regulation, we have isolated a bovine genomic clone (lambda Og15) encoding exon 1 and 15 kilobase pairs (kb) of flanking DNA. Direct RNA sequencing of the 5' end of the osteonectin message showed it contained a sequence identical to that of a 2.4-kb EcoRI-BamHI fragment located midway in the clone lambda Og15. The results indicate exon 1 is located 10 kb away from exon 2 in the bovine genome. The DNA sequence unit CCTG is repeated five times in exon 1 which is composed exclusively of untranslated sequence. Sequence analysis of the 5'-flanking DNA revealed the presence of many regulatory motifs including a "GC" box with four overlapping SP1 consensus sequences. Immediately downstream from the GC box is a 72-base pair purine-rich stretch composed primarily of direct repeats of the sequence motifs GGGGA and GGA (GAGA box). Digestion of the flanking DNA in vitro with S1 endonuclease showed a site for the enzyme at position -55 which is just 3' to the GAGA box. Chimeric chloramphenicol acetyltransferase constructs were prepared containing the S1-sensitive site and showed substantial transcriptional activity in UMR-106 and fetal and adult human bone cells which are known to be high producers of the protein. The results indicate a potential regulatory activity of the S1 site in osteonectin gene activation.

Animals↗
PubMed1989

Plasma insulin-like growth factors and bone formation in uremic hyperparathyroidism.

Bone formation in uremia is considered to be regulated in part by parathyroid hormone (PTH). However, while low levels of immunoreactive PTH are usually associated with low rates of bone formation in uremia, elevated PTH levels do not always correlate with increased bone formation. In an attempt to identify other factors that may regulate bone formation in uremic patients, we measured plasma immunoreactive insulin-like growth factors (IGF-I and IGF-II) in 15 patients who did not have aluminum-associated reductions in bone formation. Plasma levels of IGF-I but not PTH, were significantly higher in patients with high rates of bone formation when compared to patients with low or normal bone formation (P less than 0.02). While the bone formation rate at the tissue level correlated significantly with plasma PTH (r = 0.53, P less than 0.05) and IGF-I (r = 0.67, P less than 0.01), only for plasma IGF-I were there significant correlations with bone apposition (r = 0.57, P less than 0.05) and bone formation rate at the BMU level (r = 0.62, P less than 0.02), parameters which reflect mineralization activity at the cellular level. Among the static histologic parameters, osteoblastic osteoid correlated only with plasma PTH (r = 0.76, P less than 0.001), while osteoclast number correlated with both PTH (r = 0.56, P less than 0.05) and IGF-I (r = 0.67, P less than 0.01). There were no correlations between IGF-II levels and bone histology. From these data we suggest that IGF-I may promote bone formation in uremic patients with hyperparathyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Bone aluminum accumulation in hemodialysis patients: a longitudinal perspective.

Serial bone biopsies obtained from 19 chronic hemodialysis patients asymptomatic for bone disease were examined retrospectively. We found only modest amounts of stainable bone aluminum after the first few years of hemodialysis therapy. Over the ensuing 5 to 15 years, there was a progressive increase in stainable bone aluminum (% of total bone surface): 0 to 4.9 years, 19.9 +/- 3.8% (mean +/- SEM); 5.0 to 9.9 years, 28.4 +/- 5.3%; and greater than or equal to 10.0 years, 58.0 +/- 7.7%. At final biopsy, the extent of bone surface aluminum was significantly correlated with duration of hemodialysis therapy (r = 0.54) and with bone formation rate (BFR) (r = -0.54). Patients who developed aluminum-associated bone disease did not differ from other patients in duration of hemodialysis, intake of 1-hydroxylated vitamin D3 compounds, or the findings on early bone biopsy. High-turnover renal osteodystrophy remains the dominant bone lesion throughout the course of hemodialysis in patients with intact parathyroid glands. In individual patients, bone histology frequently changes over time and in some patients, aluminum-associated bone disease may improve spontaneously. Bone biopsy in an asymptomatic patient who has received hemodialysis therapy for less than 5 years does not appear to be useful in predicting the subsequent appearance of aluminum-associated bone disease.

Adult↗
PubMed1987

Early deposition of aluminum in bone in diabetic patients on hemodialysis.

Aluminum-associated bone disease is a special problem in uremic patients on hemodialysis. We have observed this disorder in uremic patients with insulin-dependent diabetes soon after the start of dialysis treatments. We therefore studied bone biopsy specimens from 18 diabetic patients on hemodialysis to determine whether aluminum accumulates on bone surfaces at an accelerated rate in diabetes. We also measured the rates of bone formation, because lower rates may enhance the accumulation of aluminum on bone surfaces. As compared with 18 nondiabetic controls with uremia who were matched for age and duration of dialysis, the patients with diabetes had a higher rate of aluminum accumulation on bone surfaces (2.1 +/- 0.7 vs. 0.4 +/- 0.2 percent per month, P less than 0.01) and a lower rate of bone formation (117 +/- 50 vs. 396 +/- 81 microns 2 per square millimeter per day, P less than 0.01). Also, the patients with diabetes whose cumulative aluminum intake exceeded 0.5 kg had higher serum aluminum levels after an infusion of deferoxamine, as compared with controls matched for aluminum intake (P less than 0.01). These measurements reflected a higher aluminum content in the whole body in patients with diabetes. We suggest that the enhanced rate of aluminum accumulation on bone surfaces in uremic patients with diabetes occurs as a result of a low rate of bone formation and an increased accumulation of aluminum in the whole body.

Aluminum↗
PubMed1987

Bone histomorphometry of renal osteodystrophy in diabetic patients.

Bone biopsies and plasma parathyroid hormone (PTH) from 27 diabetic dialysis patients were compared to biopsies and PTH levels from matched patients without diabetes to determine if PTH has a role in preserving bone mass in diabetic renal osteodystrophy. Significantly lower values were present in the diabetic group for mineralized bone area (p less than 0.003), osteoblastic osteoid (p less than 0.01), resorptive surface (p less than 0.001), fibrosis (p less than 0.005), bone apposition rate (p less than 0.01), bone formation rate (BMU level) (p less than 0.04), and plasma PTH (p less than 0.05). Bone-surface aluminum was higher in the diabetic group (44 +/- 5% vs. 20 +/- 5%, p less than 0.005). Linear regression analysis revealed significant positive correlations of mineralized bone area with time on dialysis, bone formation rate, bone resorption, and PTH only in the group without diabetes. While both groups had significant positive correlations of PTH with osteoblastic osteoid and bone resorption, only in the nondiabetic group was there a positive correlation of PTH with bone apposition and bone formation rate (BMU level), observations suggesting that the lower bone formation in the diabetic patients may have arisen in part from a failure of PTH to promote bone mineralization. We conclude that relatively low PTH levels and high bone aluminum in diabetic patients with chronic renal failure may be responsible in part for low bone mass when compared to uremic patients without diabetes.

Adult↗
PubMed1986

Comparison of parathyroid hormone assays with bone histomorphometry in renal osteodystrophy.

Bone biopsies were studied in 67 dialysis patients to determine if a PTH RIA specific for intact plasma PTH is a better predictor of osteitis fibrosa than a RIA that measures inactive carboxy-terminal/midregion plasma PTH fragments. An amino-terminal-specific antiserum that cross-reacts with intact PTH, but not midregion or carboxy-terminal fragments, and an antiserum that cross-reacts with the 44-68 region of the PTH molecule and measures both intact and midregion/carboxy-terminal PTH fragments were used in the comparisons. Plasma PTH concentrations measured by both assays correlated positively with bone formation rate, bone apposition rate, osteoblastic osteoid, osteoclast number, and marrow fibrosis. The optimum predictive value of the amino-terminal PTH assay for osteitis fibrosa was 88%, compared to 74% for the midregion PTH assay. This difference in predictive value could be attributed to the highly significant correlation of marrow fibrosis with plasma amino-terminal PTH. In conclusion, these data suggest that a PTH RIA that uses an amino-terminal-specific antiserum may be a better predictor of osteitis fibrosa in patients undergoing maintenance hemodialysis.

Bone and Bones↗