scholarly journals IGF UPTAKE WITH COMPETITIVE BINDING IN ARTICULAR CARTILAGE

2008 ◽  
Vol 16 (02) ◽  
pp. 175-195 ◽  
Author(s):  
LIHAI ZHANG ◽  
BRUCE S. GARDINER ◽  
DAVID W. SMITH ◽  
PETER PIVONKA ◽  
ALAN J. GRODZINSKY
Keyword(s):  
Articular Cartilage ◽  
Functional Groups ◽  
Dynamic Compression ◽  
Relative Proportion ◽  
Nonlinear Least Squares ◽  
Competitive Binding ◽  
Igf Binding Proteins ◽  
Bovine Articular Cartilage ◽  
Binding Preference ◽  
Igf I

Experiments on the transport of radiolabeled Insulin-like Growth Factors (IGF-I and -II) into bovine articular cartilage show differential uptake depending on the relative proportion of IGF-I and -II. In this study, we present a mathematical model describing both the transport and competition of IGF-I and -II for binding sites represented by two functional groupings of IGF binding proteins (IGFBPs). The first grouping has approximately similar binding affinity to both IGF-I and -II (i.e. IGFBPs 1–5), whereas the second group has significantly higher binding preference for IGF-II compared to IGF-I (i.e. IGFBP-6). Using nonlinear least squares, it is shown that the experimental equilibrium competitive binding results can be described using a reversible Langmuir sorption isotherm involving two dominant IGFBP functional groups.After coupling the sorption model with a poromechanical continuum model, parametric studies are carried out to investigate the effect of model changes including IGF boundary conditions and the ratios of the two IGFBP functional groups. The results show that ignoring competitive binding leads to a significant overestimation of total IGF-I uptake, but an underestimation the rate of "free" (physiologically active) IGF-I within the cartilage. An increase of first group of IGFBPs (i.e. IGFBPs 1–5) as has been reported for osteoarthritis, is observed to hinder the bioavailability of free IGF-I in cartilage, even though the total IGF-I uptake is enhanced. Furthermore, the combination of dynamic compression and competitive binding is seen to enhance the IGF-I uptake within cartilage, but this enhancement is overestimated if competitive binding is neglected.

scholarly journals Stimulation of proteoglycan biosynthesis by serum and insulin-like growth factor-I in cultured bovine articular cartilage

1986 ◽  
Vol 240 (2) ◽  
pp. 423-430 ◽  
Author(s):  
D J McQuillan ◽  
C J Handley ◽  
M A Campbell ◽  
S Bolis ◽  
V E Milway ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Growth Factor ◽  
Calf Serum ◽  
Proteoglycan Synthesis ◽  
Foetal Calf Serum ◽  
Insulin Like Growth Factor ◽  
Bovine Articular Cartilage ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

The addition of foetal calf serum to explant cultures of adult bovine articular cartilage is known to stimulate proteoglycan synthesis in a dose-dependent manner. We have now shown the activity in serum responsible for this effect to be heat- and acid-stable, to be associated with a high-Mr complex in normal serum but converted to a low-Mr form under acid conditions. The activity has an apparent Mr approximately 10,000 and isoelectric points similar to those reported for insulin-like growth factors (IGFs). Addition of a monoclonal antibody against insulin-like growth factor-I (IGF-I) prevented foetal calf serum from stimulating proteoglycan synthesis. Physiological concentrations of recombinant IGF-I or pharmacological levels of insulin when added to cartilage cultures mimicked the proteoglycan-stimulatory activity of serum. IGF-I appeared to act by increasing the rate of proteoglycan synthesis and did not change the nature of the proteoglycan synthesized nor the rate of proteoglycan catabolism by the tissue, suggesting that IGF-I may be important in the regulation of proteoglycan metabolism in adult articular cartilage. Furthermore, IGF-I can replace foetal calf serum in the culture medium, thereby allowing the use of a fully-defined medium which will maintain the synthesis and tissue levels of proteoglycan in adult articular cartilage explants for up to 5 days.

scholarly journals Contributions of the N- and C-terminal domains of IGF binding protein-6 to IGF binding

2004 ◽  
Vol 33 (2) ◽  
pp. 377-386 ◽  
Author(s):  
Stephen J Headey ◽  
Kerri S Leeding ◽  
Raymond S Norton ◽  
Leon A Bach
Keyword(s):  
Binding Affinity ◽  
Full Length ◽  
Binding Studies ◽  
Dissociation Kinetics ◽  
Igf Binding Proteins ◽  
Inhibition Of Proliferation ◽  
High Affinity ◽  
Binding Preference ◽  
Igf I ◽  
Igf Binding

Insulin-like growth factors IGF-I and IGF -II are important mediators of growth. A family of six high affinity IGF binding proteins (IGFBPs) modulate IGF action. IGFBPs have three domains, of which the N- and C-domains are involved in high affinity IGF binding. IGFBP-6 is unique in its 20–100-fold IGF-II binding specificity over IGF-I. The aim of this study was to determine the contributions of the N- and C-domains of IGFBP-6 to its IGF binding properties. We confirmed that differential dissociation kinetics are responsible for the IGF-II binding preference of IGFBP-6. The N-domain has rapid association kinetics, similar to full-length IGFBP-6, but both IGF-I and -II dissociate rapidly from this domain, thereby reducing its binding affinity for IGF-II ~50-fold. However, the N-domain binds IGF-I and -II with similar affinities and it has a similar IGF-I binding affinity to full-length IGFBP-6. This suggests that the C-domain confers the IGF-II binding preference of IGFBP-6; indeed, IGF-I bound inconsistently with very low affinity to the C-domain. Coincubation studies showed that isolated N- and C-domains of IGFBP-6 do not strongly cooperate to enhance IGF binding. The results of the binding studies are supported by the effects of the IGFBP-6 domains on IGF-induced colon cancer cell proliferation; the N-domain inhibited IGF-II induced proliferation with ~20-fold lower potency than IGFBP-6 and it was equipotent in inhibiting IGF-I- and IGF-II-induced proliferation. Coincubation of C-domain had no additional effect on N-domain-induced inhibition of proliferation. In conclusion, both the N- and C-domains of IGFBP-6 are involved in IGF binding, the C-domain is responsible for the IGF-II binding preference of IGFBP-6 and intact IGFBP-6 is necessary for high affinity IGF binding.

P188 Reduces Cell Death and IGF-I Reduces GAG Release Following Single-Impact Loading of Articular Cartilage

2008 ◽  
Vol 130 (4) ◽  
Author(s):  
Roman M. Natoli ◽  
Kyriacos A. Athanasiou
Keyword(s):  
Mechanical Properties ◽  
Cell Death ◽  
Articular Cartilage ◽  
High Impact ◽  
Individual Treatment ◽  
Joint Injury ◽  
Bovine Articular Cartilage ◽  
Treatment Type ◽  
Igf I ◽  
High Level

Prior joint injury predisposes an individual to developing post-traumatic osteoarthritis, for which there is presently no disease modifying treatment. In this condition, articular cartilage degenerates due to cell death and matrix breakdown, resulting in tissue with diminished biomechanical function. P188, a nonionic surfactant, and the growth factor IGF-I have been shown to decrease cell death. Additionally, IGF-I is known to have beneficial effects on cartilage matrix. The objective of this study was to determine the efficacy of P188, IGF-I, and their combination following articular cartilage impact injury with two energy levels, 1.1J (“low”) and 2.8J (“high”), at 24h and 1week. Bovine articular cartilage with attached underlying bone was impacted at the low or high level. Impact sites were explanted and examined immediately, or cultured for 24h or 1week in serum-free media supplemented with P188 (8mg∕ml), IGF-I (100ng∕ml), or their combination. Gross morphology, cell viability, GAG release to the media, and tissue mechanical properties were assessed. Immediately postimpact, high level impacted tissue had significantly increased gross morphology scores, indicating tissue damage, which were maintained over 1week. Gross scores following low impact were initially similar to nonimpacted controls, but, at 24h and 1week, low impact gross scores significantly increased compared to nonimpacted controls. Additionally, at 24h, high impact resulted in increased cell death, and both low and high impacts had increased GAG release compared to nonimpacted controls. Furthermore, high impact caused decreased tissue stiffness at 24h that appeared to worsen over 1week, evident by the percent decrease from nonimpacted controls increasing from 16% to 26%. No treatment type studied mitigated this loss. The combination did not perform better than either individual treatment; however, following low impact at 1week, P188 reduced cell death by 75% compared to no treatment and IGF-I decreased GAG release from the tissue by 49%. In conclusion, high impact resulted in immediate tissue changes that worsened over 1week. Though not causing immediate changes, low impact also resulted in tissue degeneration evident by 24h. No treatment studied was effective at 24h, but by 1week P188 and IGF-I ameliorated established detrimental changes occurring in articular cartilage postimpact. However, further work is needed to optimize treatment strategies to prevent and/or reverse cell death and matrix destruction in a way that maintains tissue mechanical properties, and hence its functionality.

Differential responses of IGF-I molecular complexes to military operational field training

2003 ◽  
Vol 95 (3) ◽  
pp. 1083-1089 ◽  
Author(s):  
Bradley C. Nindl ◽  
John W. Castellani ◽  
Andrew J. Young ◽  
John F. Patton ◽  
M. Javad Khosravi ◽  
...  
Keyword(s):  
Nutritional Status ◽  
Relative Proportion ◽  
Molecular Complexes ◽  
Energy Deficit ◽  
Short Term ◽  
Igf Binding Proteins ◽  
Igf I ◽  
Before And After ◽  
Term Energy ◽  
Igfbp 3

Insulin-like growth factor (IGF) I and IGF binding proteins (IGFBPs) modulate metabolic activity and tissue repair and are influenced by nutritional status. IGF-I circulates in free, ternary [IGF-I + IGFBP-3 + acid labile subunit (ALS)], and binary (IGF-I + IGFBP) molecular complexes, and the relative proportions regulate IGF-I extravascular shifting and bioavailability. This study examined the hypothesis that sustained physical activity and sleep deprivation superimposed on a short-term energy deficit would alter the IGFBP concentrations and alter the proportions of IGF-I circulating in ternary vs. binary molecular complexes. Components of the IGF-I system (total and free IGF-I; IGFBP-1, -3, and ALS; nonternary IGF-I and IGFBP-3), biomarkers of metabolic and nutritional status (transferrin, ferritin, prealbumin, glucose, free fatty acids, glycerol, β-hydroxybutyrate), and body composition were measured in 12 men (22 ± 3 yr, 87 ± 8 kg, 183 ± 7 cm, 20 ± 5% body fat) on days 1, 3, and 4 during a control and experimental (Exp) period. During Exp, subjects performed prolonged work (energy expenditure of ∼4,500 kcal/day) with caloric (1,600 kcal/day) and sleep (6.2 h total) restriction. IGF-I and IGFBP-3 were measured by immunoassay before and after immunoaffinity depletion of ALS-based complexes (i.e., ternary complex removal). Exp produced losses in body mass (-3.0%), lowered total IGF-I (-24%), free IGF-I (-42%), IGFBP-3 (-6%), nonternary IGF-I (-27%), and IGFBP-3 (-16%), and increased IGFBP-1 (256%). No Exp effects were observed for ALS. No changes were observed in the proportion of IGF-I circulating in free (∼1.2%), ternary (∼87.4%), or nonternary (∼11.4%) molecular complexes. During Exp, glucose concentrations were lower on day 3, but days 1 and 4 were statistically similar. In conclusion, during a short-term energy deficit in young, healthy men, 1) IGF-I system components differentially respond (both in direction and magnitude) to a given metabolic perturbation and 2) the relative proportion of IGF-I sequestered in ternary vs. nonternary molecular complexes appears to be well maintained.

scholarly journals Intermittent Dynamic Compression Confers Anabolic Effects in Articular Cartilage

2021 ◽  
Vol 11 (16) ◽  
pp. 7469
Author(s):  
Amalie Engstrøm ◽  
Frederik S. Gillesberg ◽  
Solveig S. Groen ◽  
Peder Frederiksen ◽  
Anne-Christine Bay-Jensen ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Mechanical Loading ◽  
Kinase Inhibitor ◽  
Dynamic Compression ◽  
Compressive Loading ◽  
Type Ii Collagen ◽  
Cartilage Explants ◽  
Type Ii ◽  
Bovine Articular Cartilage ◽  
Collagen Formation

(1) Background: Mechanical loading is an essential part of the function and maintenance of the joint. Despite the importance of intermittent mechanical loading, this factor is rarely considered in preclinical models of cartilage, limiting their translatability. The aim of this study was to investigate the effects of intermittent dynamic compression on the extracellular matrix during long-term culture of bovine cartilage explants. (2) Methods: Bovine articular cartilage explants were cultured for 21 days and subjected to 20 min of 1 Hz cyclic compressive loading five consecutive days each week. Cartilage remodeling was investigated in the presence of IGF-1 or TGF-β1, as well as a TGF-β receptor 1 (ALK5) kinase inhibitor and assessed with biomarkers for type II collagen formation (PRO-C2) and fibronectin degradation (FBN-C). (3) Results: Compression of cartilage explants increased the release of PRO-C2 and FBN-C to the conditioned media and, furthermore, IGF-1 and compression synergistically increased PRO-C2 release. Inhibition of ALK5 blocked PRO-C2 and FBN-C release in dynamically compressed explants. (4) Conclusions: Dynamic compression of cartilage explants increases both type II collagen formation and fibronectin degradation, and IGF-1 interacts synergistically with compression, increasing the overall impact on cartilage formation. These data show that mechanical loading is important to consider in translational cartilage models.

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