Growth factors in asymptomatic osteoarthritis - insulin, insulin-like growth factor-1, growth hormone

Denko, Charles W.; Boja, Betty

doi:10.1007/bf02663743

Cited by 33 publications

(63 citation statements)

References 10 publications

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“…These include penetration of stimulatory mediators from the synovial fluid, local production of mediators, or mechanical factors. In the former case, circulating levels of growth hormone are reported to increase in OA individuals (27). Therefore, the upregulation in IGFI expression by OA chondrocytes may be regulated, at least in part, by a growth hormone-dependent mechanism.…”

Section: Discussionmentioning

confidence: 97%

Insulin-like growth factor (IGF) receptor, IGF-I, interleukin-1 beta (IL-1 beta), and IL-6 mRNA expression in osteoarthritic and normal human cartilage.

Middleton¹,

Manthey²,

Tyler³

1996

J Histochem Cytochem.

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Insulin-like growth factor-I (IGF-I) stimulates the production of extracellular matrix by cartilage cells and this action is mediated through the Type 1 IGF receptor. Expression of the genes for the IGF receptor and for IGF-I was examined in normal and osteoarthritic (OA) human articular cartilage by in situ hybridization. RNA transcripts for Type 1 receptor were detected in all 73 tissue samples and in 80-100% of chondrocytes per section. Signal for the receptor was present in normal and OA cells, and the highest message levels were in the tissues exhibiting advanced pathology. Strong message signals in the ceUs of the more advanced lesionS were also noted for IGF-I, whereas little or no IGF-I mRNA was IntroductionArticular cartilage consists of chondrocytes embedded in an extensive extracellular matrix. These cells synthesize, organize, and regulate the deposition of their surrounding matrix, and in normal mature tissue they actively maintain a stable equilibrium between synthesis and degradation of matrix molecules. In disease states such as osteoarthritis (OA), the stable equilibrium is disrupted, leading eventually to complete loss of cartilage from the joint surface. Reports of altered phenotypic expression in human OA chondrocytes include production of Type 111 and Type X collagen (I), the detection of novel chondroitin sulfate epitopes attached to aggrecan (2), progressive loss of extracellular matrix, and the formation of clonal cell clusters in depleted regions (3).Insulin-like growth factors (IGFs) or somatomedins regulate the growth and differentiation of a variety of tissues and are implicated in their hypertrophy and repair (4). They are bound in vivo to specific binding proteins (IGF BP 1-6) which extend the half-life of the growth factor and modulate its activity (5). Traditionally, IGF-I Supported by the Nuffield Foundation (Oliyr Bird Fund) and by the Arthritis and Rheumatism Council.Correspondence tu James Middleton, PhD, Dept. of General Dermatology, Sandot Forschungsinstitut, Brunnerstr. 59, A-1235 Vienna, Austria. was considered to be mainly produced in the liver and to mediate the actions of growth hormone on target tissues (endocrine function). However, it is now clear that IGFI is synthesized by many cells of mesenchymal origin in different tissues, indicating a local function involving autocrinelparacrine mechanisms. IGFI is a major anabolic growth factor in the regulation of articular cartilage metabolism in vitro (6,7). It also stimulates the growth of epiphyseal cartilage in vivo (8). Rat epiphysial chondrocytes express the IGF-I gene, and locally produced IGFI is implicated in stimulating clonal expansion of these cells (9). In a previous study we showed that chondrocytes in human articular cartilage also express IGFI mRNA. Very low amounts were detected in normal samples, whereas enhanced levels, four-to fivefold higher, were evident in cells from OA cartilage that had formed clusters at fibrillated sites (10). The metabolic and mitogenic action of IGFs are believed to be mediated...

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Section: Discussionmentioning

confidence: 97%

Insulin-like growth factor (IGF) receptor, IGF-I, interleukin-1 beta (IL-1 beta), and IL-6 mRNA expression in osteoarthritic and normal human cartilage.

Middleton¹,

Manthey²,

Tyler³

1996

J Histochem Cytochem.

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“…Since previous studies have shown that 1) IGF-1 reduces the degradation of normal cartilage in vitro by its direct action on decreasing both the basal and the cytokine-stimulated degradation of proteoglycans (29,30), 2) serum IGF-1 levels appear to be reduced in OA (31) and in juvenile chronic arthritis (32), and 3) synovial fluid levels of IGF-1 are decreased in various arthritides (33), one may be tempted to conclude that a decrease in the availability of this anabolic factor may be responsible for the persistence of the osteoarthritic condition. However, recent findings showing the increased synthesis of IGF-1 by OA chondrocytes (34) combined with the enhancement of IGF-1 in the matrix and IGF-1 mRNA in chondrocytes of the superficial layer of human OA articular cartilage (35) render this hypothesis very unlikely.…”

Section: Discussionmentioning

confidence: 99%

Human Osteoarthritic Chondrocytes Possess an Increased Number of Insulin‐Like Growth Factor 1 Binding Sites but are Unresponsive to its Stimulation

Doré

Pelletier

DiBattista

et al. 1994

Arthritis & Rheumatism

186

117

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Objective. To characterize the insulin-like growth factor 1 (IGF-1) receptor in human osteoarthritic (OA) and normal adult chondrocytes. The biologic response of chondrocytes to IGF-1 stimulation was examined, as was the presence and synthesis of IGF binding proteins (IGFBP) in these cells.Methods. Binding studies, Northern blot, immunohistochemical analysis, and affinity cross-linking experiments were performed for characterization of the IGF receptor, and the latter method was also used for IGFBP determination. The biologic response was estimated via the incorporation of radiolabeled proline into a newly synthesized protein.Results histochemical studies with a monoclonal antibody (MAb) against the type 1 IGF receptor (aIR3) showed increased staining in OA cartilage compared with normal tissue. Biologic responses of chondrocytes after IGF-1 stimulation revealed that OA chondrocytes were unresponsive, whereas a 2.5-fold increase in new protein synthesis was observed in normal cells. Competition studies in normal chondrocytes revealed that both IGF-1 and IGF-2 displaced radiolabeled IGF-1 in a comparable manner; however, insulin at high concentration weakly competes. Moreover, MAb aIR3 effectively blocked specific binding in normal chondrocytes (77 %), but not in OA chondrocytes (26%). Northern blot and covalent cross-linking analyses revealed the specific band characteristic of type 1 receptor. With the latter technique, other bands corresponding to the IGFBPs were also detected. Comparison between normal and OA chondrocytes showed increased intensity of the IGFBP bands, particularly those corresponding to the IGFBP-3 doublet.Conclusion. It is shown that type 1 IGF receptor is expressed in human articular cartilage and that the level of binding sites is significantly increased in OA chondrocytes. Interestingly, despite the higher level of binding sites in OA cells, no response to IGF-1 stimulation was found in these cells. Our data suggest that this increase in specific binding may involve not only the type 1 IGF receptor but also IGFBP on the cell surface. The latter, by binding the IGF-1, will diminish the bioavailability of IGF-1 and thus prevent its anabolic action.Osteoarthritis (OA) is the most common of the various arthritic disorders affecting humans. The dis-

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“…This is widely regarded as a paracrine and autocrine attempt at autoinductive cartilage repair. However, in ongoing disease there is a subsequent decline in IGF-I content, coinciding with more extensive cartilage loss [5]. These local changes are also reflected in decreased serum IGF-I levels, which some propose as a marker of OA severity [6,7,46].…”

Section: Introductionmentioning

confidence: 99%

Exogenous insulin‐like growth factor‐I stimulates an autoinductive IGF‐I autocrine/paracrine response in chondrocytes

Nixon

Saxer

Brower-Toland

2001

Journal Orthopaedic Research

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The modulation of insulin-like growth factor-I (IGF-I) gene expression by chondrocytes following exogenous IGF-I supplementation of culture was assessed to examine the hypothesis that constitutive IGF-I mRNA activity is suppressed by exogenous administration of IGF-I to cartilage in situ. Chondrocytes in monolayer culture were treated with 0, 10 or 100 ng/ml IGF-I for 48 h and resultant IGF-I and matrix gene expression patterns were assessed by quantitative polymerase chain reaction (qPCR) and northern blotting, respectively. Effective translation of proteoglycan (PG) as a response to IGF-I was determined by dimethylmethylene blue (DMMB) dye-binding assay. To determine the temporal nature of the IGF-I autocrine/paracrine response to exogenous IGF-I, chondrocyte cultures were treated with 100 nglml IGF-I and the IGF-I mRNA response was assessed at 0,4, 12,24,48 and 72 h. Significant increases in chondrocyte density and in PG synthesis occurred during treatment of chondrocyte cultures with 10 and 100 ng/ml IGF-I. Persistent exposure of chondrocytes to 100 ng/ml IGF-I resulted in maximal IGF-1 mRNA response at 24 h, with declining message accumulation at 48 and 72 h. These data suggest that IGF-I induces an autoinductive IGF-I autocrinel paracrine transcriptional response. The clinical ramifications of these findings include support for the use of exogenous IGF-I for cartilage repair where it could conceivably amplify and extend the effect of exogenous IGF-I beyond the transitory persistence of supplemental IGF-I ligand in repair constructs.

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Growth factors in asymptomatic osteoarthritis - insulin, insulin-like growth factor-1, growth hormone

Cited by 33 publications

References 10 publications

Insulin-like growth factor (IGF) receptor, IGF-I, interleukin-1 beta (IL-1 beta), and IL-6 mRNA expression in osteoarthritic and normal human cartilage.

Insulin-like growth factor (IGF) receptor, IGF-I, interleukin-1 beta (IL-1 beta), and IL-6 mRNA expression in osteoarthritic and normal human cartilage.

Human Osteoarthritic Chondrocytes Possess an Increased Number of Insulin‐Like Growth Factor 1 Binding Sites but are Unresponsive to its Stimulation

Exogenous insulin‐like growth factor‐I stimulates an autoinductive IGF‐I autocrine/paracrine response in chondrocytes

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