scholarly journals Intact IGF-Binding Protein-4 and -5 and Their Respective Fragments Isolated from Chronic Renal Failure Serum Differentially Modulate IGF-I Actions in Cultured Growth Plate Chondrocytes

2001 ◽  
Vol 12 (11) ◽  
pp. 2400-2410
Author(s):  
DANIELA KIEPE ◽  
DENNIS L. ANDRESS ◽  
SUBBURAMAN MOHAN ◽  
LUDGER STÄNDKER ◽  
TIM ULINSKI ◽  
...  
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Growth Plate Chondrocytes ◽  
Chondrocyte Proliferation ◽  
Amino Terminal ◽  
Growth Cartilage ◽  
Terminal Fragment ◽  
Igf I ◽  
Igf Binding ◽  
Amino Terminal Fragment

Abstract. Impairment of longitudinal growth among children with chronic renal failure (CRF) may be partly attributable to the inhibition of insulin-like growth factor (IGF) activity by an excess amount of high-affinity IGF-binding proteins (IGFBP). Elevated levels of immunoreactive IGFBP-4 in CRF serum are inversely correlated with the standardized heights of these children, whereas levels of IGFBP-5, which circulates mainly as proteolyzed fragments, are positively correlated with growth parameters. To delineate the respective effects of these IGFBP on growth cartilage, the biologic effects of intact and fragmented forms of IGFBP-4 and IGFBP-5 on rat growth plate chondrocytes in primary cultures were characterized. Intact IGFBP-4 and IGFBP-5 and the amino-terminal fragment IGFBP-51-169 were recombinant proteins; the carboxy-terminal fragments IGFBP-5144-252 and IGFBP-4136-237 and the amino-terminal fragment IGFBP-41-122 were purified to homogeneity from CRF hemofiltrates. Intact IGFBP-4 and, to a lesser extent, IGFBP-41-122 inhibited IGF-I-induced cell proliferation. In contrast, intact IGFBP-5 was stimulatory in the absence or presence of exogenous IGF-I, whereas the amino-terminal fragment IGFBP-51-169 was inhibitory. Studies on the mechanism by which IGFBP-4 and IGFBP-5 exert opposite effects on chondrocyte proliferation demonstrated that intact IGFBP-4 prevented the binding of 125I-IGF-I to chondrocytes, whereas intact IGFBP-5 enhanced ligand binding and was able to bind specifically to the cell membrane. These data suggest that intact IGFBP-4 and, to a lesser extent, IGFBP-41-122 act exclusively as growth-inhibitory binding proteins in the growth cartilage. IGFBP-5, however, can either stimulate (if it remains intact) or inhibit (if amino-terminal forms predominate) IGF-I-stimulated chondrocyte proliferation.

scholarly journals MANAGEMENT OF ENDOCRINE DISEASE: Novel anabolic treatments for osteoporosis

2018 ◽  
Vol 178 (2) ◽  
pp. R33-R44 ◽  
Author(s):  
Ernesto Canalis
Keyword(s):  
Growth Factor ◽  
Bone Formation ◽  
Vertebral Fractures ◽  
Mineral Density ◽  
Anabolic Agents ◽  
Amino Terminal ◽  
Terminal Fragment ◽  
Igf I ◽  
And Function ◽  
Amino Terminal Fragment

Skeletal anabolic agents enhance bone formation, which is determined by the number and function of osteoblasts. Signals that influence the differentiation and function of cells of the osteoblast lineage play a role in the mechanism of action of anabolic agents in the skeleton. Wnts induce the differentiation of mesenchymal stem cells toward osteoblasts, and insulin-like growth factor I (IGF-I) enhances the function of mature osteoblasts. The activity of Wnt and IGF-I is controlled by proteins that bind to the growth factor or to its receptors. Sclerostin is a Wnt antagonist that binds to Wnt co-receptors and prevents Wnt signal activation. Teriparatide, a 1–34 amino terminal fragment of parathyroid hormone (PTH), and abaloparatide, a modified 1–34 amino terminal fragment of PTH-related peptide (PTHrp), induce IGF-I, increase bone mineral density (BMD), reduce the incidence of vertebral and non-vertebral fractures and are approved for the treatment of postmenopausal osteoporosis. Romosozumab, a humanized anti-sclerostin antibody, increases bone formation, decreases bone resorption, increases BMD and reduces the incidence of vertebral fractures. An increased incidence of cardiovascular events has been associated with romosozumab, which is yet to be approved for the treatment of osteoporosis. In conclusion, cell and molecular studies have formed the foundation for the development of new anabolic therapies for osteoporosis with proven efficacy on the incidence of new fractures.

Effects of chronic renal failure on plasma clearance of insulin-like growth factor I, des-(1-3)IGF-I, and LR3IGF-I

1996 ◽  
Vol 271 (4) ◽  
pp. E649-E657 ◽  
Author(s):  
C. M. Gillespie ◽  
S. J. Hazel ◽  
P. E. Walton ◽  
A. A. Martin
Keyword(s):  
Molecular Weight ◽  
Renal Failure ◽  
Chronic Renal Failure ◽  
Growth Factor ◽  
Insulin Like Growth Factor ◽  
Total Clearance ◽  
Factor I ◽  
Igf I ◽  
Igf Binding ◽  
Growth Factor I

Using a rat model of chronic renal failure (CRF), we examined insulin-like growth factor I (IGF-I) clearance, degradation, organ distribution, and IGF binding profiles in plasma. The effects of IGF-binding proteins (IGFBP) on IGF clearance and degradation in CRF were studied using the IGF-I analogues des-(1-3)IGF-I and LR3IGF-I, which bind poorly to IGFBP. Although total clearance of IGF-I was not significantly altered in CRF, half-life and area under the curve were increased in the rapid distribution phase and were reduced in the slow elimination phase. Total clearance of LR3IGF-I was significantly increased. Reduced binding of IGF-I in the 150-kDa complex and increased binding to smaller-molecular-weight IGFBP were observed in CRF. Increased degradation of both IGF-I and LR3IGF-I was associated with reduced IGF binding in the 150-kDa complex. The results suggest that the accumulation of lower-molecular-weight IGFBP with reduced IGF binding in the 150-kDa complex, associated with increased degradation of peptide, may explain, at least in part, the reduced bioactivity of IGF-I observed in CRF.

scholarly journals Evolution of the hedgehog Gene Family

Genetics ◽  
1996 ◽  
Vol 142 (3) ◽  
pp. 965-972 ◽  
Author(s):  
Sudhir Kumar ◽  
Kristi A Balczarek ◽  
Zhi-Chun Lai
Keyword(s):  
Intercellular Communication ◽  
Short Range ◽  
Gene Duplications ◽  
Future Directions ◽  
Amino Terminal ◽  
Terminal Fragment ◽  
Carboxyl Terminal ◽  
Multicellular Organisms ◽  
Amino Terminal Fragment

Abstract Effective intercellular communication is an important feature in the development of multicellular organisms. Secreted hedgehog (hh) protein is essential for both long- and short-range cellular signaling required for body pattern formation in animals. In a molecular evolutionary study, we find that the vertebrate homologs of the Drosophila hh gene arose by two gene duplications: the first gave rise to Desert hh, whereas the second produced the Indian and Sonic hh genes. Both duplications occurred before the emergence of vertebrates and probably before the evolution of chordates. The amino-terminal fragment of the hh precursor, crucial in long- and short-range intercellular communication, evolves two to four times slower than the carboxyl-terminal fragment in both Drosophila hh and its vertebrate homologues, suggesting conservation of mechanism of hh action in animals. A majority of amino acid substitutions in the amino- and carboxyl-terminal fragments are conservative, but the carboxyl-terminal domain has undergone extensive insertion-deletion events while maintaining its autocleavage protease activity. Our results point to similarity of evolutionary constraints among sites of Drosophila and vertebrate hh homologs and suggest some future directions for understanding the role of hh genes in the evolution of developmental complexity in animals.

The amino‐terminal fragment of human urokinase directs a recombinant chimeric toxin to target cells: internalization is toxin mediated

1997 ◽  
Vol 11 (13) ◽  
pp. 1169-1176 ◽  
Author(s):  
M. Serena Fabbrini ◽  
Daniela Carpani ◽  
Iraldo Bello‐Rivero ◽  
Marco R. Soria
Keyword(s):  
Target Cells ◽  
Amino Terminal ◽  
Terminal Fragment ◽  
Amino Terminal Fragment

Parathyroid hormone metabolism and its potential as a uremic toxin

1980 ◽  
Vol 239 (1) ◽  
pp. F1-F12 ◽  
Author(s):  
E. Slatopolsky ◽  
K. Martin ◽  
K. Hruska
Keyword(s):  
Renal Failure ◽  
Parathyroid Hormone ◽  
Chronic Renal Failure ◽  
Biological Effects ◽  
Uremic Toxin ◽  
Terminal Portion ◽  
Single Chain ◽  
Biochemical Alterations ◽  
Amino Terminal ◽  
Carboxy Terminal

Secondary hyperparathyroidism is a universal complication of chronic renal failure. It has been proposed that the markedly elevated levels of immunoreactive parathyroid hormone (i-PTH) in uremia may represent a “uremic toxin” responsible for many of the abnormalities of the uremic state. Plasma i-PTH consists of a mixture of intact hormone, a single-chain polypeptide of 84 amino acids, and smaller molecular weight hormonal fragments from both the carboxy- and amino-terminal portion of the PTH molecule. The hormonal fragments arise from metabolism of intact PTH by peripheral organs as well as from secretion of fragments from the parathyroid glands. The structural requirements for the known biological actions of PTH reside in the amino-terminal portion of the PTH molecule. Carboxy-terminal fragments, biologically inactive at least in terms of adenylate cyclase activation, hypercalcemia, or phosphaturia, depend on the kidney for their removal from plasma, and thus accumulate in the circulation in chronic renal failure. It is unknown at the present time if other biological effects of these carboxy-terminal fragments may contribute to some of the biochemical alterations observed in uremia. The most significant consequence of increased PTH levels in uremia is the development of bone disease characterized by osteitis fibrosa. In addition, it would appear that PTH plays an important role in some of the abnormal electroencephalographic patterns observed in uremia. This may be due to a potential role of PTH in increasing calcium content of brain. Parathyroid hormone also has been implicated as a pathogenetic factor in many other alterations present in uremia, i.e., peripheral neuropathy, carbohydrate intolerance, hyperlipidemia, and other alterations. Unfortunately, outstanding clinical research is lacking in this field and conclusive experimental data are practically nonexistent. Further studies are necessary if one is to accept the concept of PTH being a significant “uremic toxin.”

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