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.

Abstract

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...

Regulation of the friction coefficient of articular cartilage by TGF‐β1 and IL‐1β

“…The destruction of the articular cartilage matrix by IL-1b is a well-known effect that produces characteristic damage features attributable to surface erosion. 15,29 IL-1b has been partly implicated in cartilage matrix degradation by enhancing the expression of matrix metalloproteinases (MMPs) 14,30 and aggrecanases. 29 Furthermore, there is evidence that IL-1b and TNF-a colocalize with MMPs in the superficial layer of the arthritic cartilage, revealing a key role of this layer in the pathogenesis of arthritic diseases.…”

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

“…In the physis at least, the contribution of IGF-I ligand to chondrocyte proliferation and matrix elaboration are derived from both circulating endocrine sources and local autocrine/paracrine IGF-I production, particularly in the adolescent [4,17,18, 3 1,421. Increased IGF-I expression in osteoarthritic tissues has also been described focally in chondrocyte clones or clusters [24,25,33], and a generalized increase in cartilage IGF-I content is also seen in early OA [44]. Similarly, IGF-I expression is elevated in other cartilage diseases such as osteochondrosis/dyschondroplasia, which may be initiating reparative phases [37,47].…”

“…Intermediate times to selected assay points were not evaluated; however, it is apparent that the response was later than previously described for TGF-P, where an autocrine response to TGF-P1 was evident within 4 h, and had peaked 12 h after exposure to TGF-PI [l]. Constitutive IGF-I production in cartilage is well documented in chondrocytes from the physis, and reduced expression is described in articular cartilage [23,24,27]. In the physis at least, the contribution of IGF-I ligand to chondrocyte proliferation and matrix elaboration are derived from both circulating endocrine sources and local autocrine/paracrine IGF-I production, particularly in the adolescent [4,17,18, 3 1,421.…”

Evidence for a key role of leptin in osteoarthritis

“…High levels of IGF-1 and TGF␤ were indeed measured in the SF from patients with OA (46,47), and synthesis of these growth factors was increased in human OA cartilage (48)(49)(50) as well as in animal models of OA (33,51). These growth factors are believed to have a beneficial function in the cartilage repair process that may occur during OA (51)(52)(53).…”