M.E.Müller Institut für Biomechanik, University of Bern, 3010 Bern, Switzerland
Keywords: human; bone, cartilage; pharmacology; arthritis; reduction; toxicity testing: pharmaceuticals
Duration: 3 years Project Completion: 1999
Background and Aim
Osteoarthritic and rheumatoid joint diseases are widespread in the Western population, especially among the elderly. Novel and improved treatment concepts are continually being developed in vitro and evaluated. Evaluations require both the availability of in vitro screening systems for the discovery of promising new drugs and therapeutic approaches. The usefulness of such in vitro studies depends heavily upon the extent to which they accurately mimic conditions within normal human tissue.
Although the basic composition of articular cartilage is known, its detailed structural organization in adult humans has not been extensively studied. It is therefore the purpose of this study to quantitatively analyze and provide a definition of the structural organization and variation within adult human articular cartilage tissue. This information would provide essential reference points for the development of in vitro conditions that closely simulate conditions in vivo and contributes to a database with the detailed structural organization of the human adult articular cartilage.
Method and Results
Adult human articular cartilage tissue was acquired from adult (age 20-40) human bodies within 48 hours of death of individuals without a history of joint disease. This tissue was then subjected to chemical fixation and morphometric analysis using confocal laser scanning microscopy. Morphological parameters quantified included tissue size, cellularity, cell volumes, and matrix volume per cell, all determined as functions of the zone (depth) within the articular cartilage. Nine different topographical sites of the human knee and ankle joints were analyzed for comparisons between anatomical locations.
It was found that the tissue thickness varies considerably between topographic locations in human joints. Moreover, the cellularity of the tissue was found to be, compared to animal tissues, extremely low (1.6 %). The cell-controlled matrix domains around individual cells varied on the order of 2 to 3 times between different zones in the joint cartilage, as well as between different regions in the joints. Mean chondrocyte cell volumes were found to vary between 1'200 and 20'000 cubic micrometers, whereas the mean matrix volumes per cell varied between 6'000 to 15'000 cubic micrometers. Significant differences in structural organization between different topographical sites were also encountered.
Conclusions and Relevance for 3R
The quantitative data gleaned from these studies allows precise simulation in vitro of the in vivo conditions of the human joint cartilage and will therefore improve the relevance of in vitro results, helping to reduce the necessity of animal experiments. Moreover, the data points out that the cellular and structural relationships in the human tissue are fundamentally different from those found in animal models. Thus future experimental designs will require appropriate adaptation. These results will help to optimize experimental screening conditions for new drug development for the treatment and prevention of articular cartilage diseases.
1, Hunziker E.B., Quinn T.M. and Häuselmann, H.J. (2002) Quantitative structural organization of normal adult human articular cartilage. Osteoarthritis and Cartilage, 10: 564 - 572.