DOI: 10.1097/01.blo.0000144979.73030.fe

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Issn Print: 0009-921X

Publication Date: 2004/10/01


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Nonsurgical Disease-Modifying Interventions

R Lane Smith

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Excerpt

Of the nonsurgical interventions in treating osteoarthritis, the most direct approach involves the application of electric signals. The rationale for electrical stimulation for cartilage rests with studies that document the presence of zeta potentials and voltage gradients in the tissue that result from the charge properties of the macromolecular constituents. The challenges in the field are to determine the mechanisms by which electric effects alter chondrocyte metabolism. There is a need to define the electric fields that exist in articular cartilage and within the cells. The quantification of the electric fields in the cells will require technical advances in instrumentation. The existence of such tools will allow measurement of tissue, cell, and intracellular field strengths.
Evaluation of nonsurgical disease-modifying interventions can be achieved using biologic markers. For example, a specific biologic molecule like Type II collagen always is associated with articular cartilage. Therefore, Type II collagen can be used to track alterations involving chondrogenesis. A requirement of a marker is that, when used, it must reflect the status of the constituent it represents. For example, if one were to follow the differentiation of pluripotent mesenchymal cells, initially the cells would not express any Type II collagen. However, if these cells differentiate into chondrocytes, the expectation would be that the marker, Type II collagen, would be apparent.
Markers used to investigate diseased states, for example in osteoarthritis (OA), must have proof that the bioresponse reflects the status of the targeted tissue, for example, articular cartilage, synovium, and others. Not all markers are of equal value. The challenge is to test for the best marker in the finest system to identify upstream and downstream regulators. The differentiation of upstream and downstream events especially is useful to understanding disease development. Markers play a key role in sorting out these events
The future progress in understanding OA will include establishing interactions and control of upstream regulators. These regulators include transcription factors with an established association to chondrocyte gene products such as Sox9 and NFAT. Other areas worthy of attention include transcription complex accessory proteins and modifiers of chromatin structure that alter the accessibility of DNA.
Downstream regulators are recognized as encompassing intracellular kinases including the kinase kinases and kinase-kinase kinases. These intracellular enzymes may be subject to substantial levels of cross-talk and compensation for missing steps. Care is required in interpretation of results with inhibitor studies before applicable efficacy for clinical use can be concluded. The precise role of phosphorylation and phosphatase activity in these regulatory pathways needs to be established to assess steps in control of OA. Other downstream modulators include cell surface receptors such as CD44 for hyaluronan, integrins for cell matrix proteins, pericellular matrix collagens (eg, Type VI collagen), and integral membrane channel proteins. The role of organizational matrix molecules such as Type IX and Type XI collagen in the feedback on cell metabolism is an important downstream event in cartilage maintenance and repair.
The assessment of cellular catabolic and anabolic activities with aging is important to the health and fitness of cartilage performance. The question remains as to when aging of cartilage begins. There is a need for theoretical models that reproduce rates of change in cartilage metabolism, which in turn could be verified in animal models.
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