The signs of differentiation of chondrocytes in the formation of early cartilage lesions in the elderly

Objective. To study the relationship between the activity of collagen type II cleavage and the pattern of expression of the genes responsible for chondrocyte differentiation in the areas of intact cartilaginous tissue and in those of early focal cartilage lesions similar to those observed in elderly people with osteoarthrosis (OA).
Material and methods. The distal femoral articular surface of the knee joint that articulated with the patella and had focal lesions was examined in the elderly. Collagen type II cleavage was estimated by enzyme immunoassay. Gene expression was determined with reverse-transcription polymerase chain reaction.
Results. The activity of collagen type II cleavage was shown to be increased in the area of age-related OA-like cartilage lesions. This was accompanied by the high expression of collagenases of metalloproteinases (MMP) 1, 14 (MT1-MMP), aggrecanases - desintegrin and MMP with thrombospondin type 1 motif (ADAMTS) 5, the cytokines of interleukins (IL) 1α/β and tumor necrosis factor-α (TNF-α), as well as the genes associated with chondrocyte hypertrophy of type X collagen (C0L10A1), MMP 13 and 9, Indian hedgehog (Ihh) and cas-pase 3 in the immediate vicinity of a lesion area. At the same time, there was a high expression of growth factors associated with the proliferation phase of chondrocytes, namely: parathyroid hormone-related peptide (PTHrP), fibroblast growth factor-2 (FGF-2), transforming growth factor β1/2 (TGF-β1/2), as well as macromolecules of matrix of type II collagen (C0L2A1) and aggrecan in both the areas adjacent to the lesions and at a considerable distance from their center. However, these areas showed no higher collagen cleavage activity. Nether higher collagen cleavage, nor excess expression of the genes examined were observed in the absolutely intact cartilage areas. Conclusion. Our studies have indicated that the area of very early age-related OA-like focal cartilage lesions exhibits enhanced type II collagen cleavage that is attended by the expression of the genes associated with chondrocyte differentiation in the embryonic growth plate.

articular cartilage, chondrocyte differentiation, gene expression, focal lesions

1. <div><p>Poole A.R., Howell D.S. Etiopathogenesis of osteoarthritis. In: Moskowitz R.W., Howell D.S., Goldberg V.M., Mankin H.J., eds. Osteoarthritis: Diagnosis and Management. 3rd ed. Philadelphia: W.B. Saunders Co, 2001: 29-47.</p><p>Billinghurst R.C., Dahlberg L., Ionescu M. et al. Enhanced cleavage of type II collagen by collagenases in osteoarthritic cartilage. J Clin Invest 1997; 99: 1534-45.</p><p>Dahlberg L., Billinghurst R.C., Manner P. et al. Selective enhancement of collagenasemediated cleavage of resident type II collagen in cultured osteoarthritic cartilage and arrest with a synthetic inhibitor that spares collagenase (matrix metalloproteinase). Arthr Rheum 2000; 43: 673-82.</p><p>Wu W., Tchetina E., Mwale F. et al. Proteolysis involving MMP-13 (collagenase- 3) and the expression of the chondrocyte hypertrophic phenotype. J Bone Miner Res 2003; 7: 639-51.</p><p>Huebner J.L., Otterness I.G., Freund E.M. et al. Collagenase-1 and collagenase-3 expression in guinea pig model of osteoarthritis. Arthr Rheum 1998; 41: 877-90.</p><p>Squires G.R., Pidoux I., Okouneff S. et al. The development of focal lesions in ageing human articular cartilage involves molecular changes in type II collagen and aggrecan characteristic of osteoarthritis. Arthr Rheum 2002; 48: 1261-70.</p><p>Poole A.R. Cartilage in health and disease. In: Koopman W., ed. Arthritis and Allied Conditions. A textbook of rheumatology.14th ed. Philadelphia: Lippincott, Williams &amp; Wilkins, 2001; 226-84.</p><p>Tchetina E.V., Mwale F., Poole A.R. Distinct phases of coordinated early and late gene expression in growth plate chondrocytes in relationship to cell proliferation, matrix assembly, remodelling, and cell differentiation. J Bone Miner Res 2003; 18: 844-51.</p><p>Mankin H.J., Dorfman H., Lipello L. et al. Biochemical and metabolic abnormalities in articular cartilage from osteoarthritic human hips. II. Correlation of biochemical and metabolic data. J Bone Joint Surg Am 1971; 3: 23-37.</p><p>Dean D.D., Azzo W., Martel-Pelletier J. et al. Evidence for metalloproteinase and metalloproteinase inhibitor imbalance in human osteoarthritic cartilage. J Clin Invest 1989; 84: 678-85.</p><p>Caterson B., Flannery C.R., Hughes C.E. et al. Mechanisms involved in cartilage proteoglycan catabolism. Matrix Biol 2000; 19: 333-44.</p><p>Aigner T., McKenna L. Molecular pathology and pathobiology of osteoarthritic cartilage. Cell Mol Life Sci 2002; 14: 578-84.</p><p>Kuhn K., D'Lima D.D., Hashimoto S. et al. Cell death in cartilage. Osteoarthr Cartilage 2004; 12: 1-16.</p></div><br />