Markers of Osteoarthritis: Implications for Early Diagnosis and Monitoring of the Pathological Course and Effects of Therapy

Chapter 62Markers of Osteoarthritis


Implications for Early Diagnosis and Monitoring of the Pathological Course and Effects of Therapy



David D. Frisbie


Although joint disease can be diagnosed using routine clinical methods, more accurate and earlier diagnosis may lead to identification of osteoarthritis (OA) before irreversible changes occur within joint tissues. Measuring levels of molecular products of tissue turnover, known as biomarkers, from healthy and diseased cartilage and bone has the potential to achieve early diagnosis and allow a better understanding of the pathophysiology of OA. The potential also exists to monitor disease, especially in response to novel therapeutic agents. Work with biomarkers of articular cartilage and bone in people and horses with OA has yielded promising results. This chapter discusses some of the markers that currently are being evaluated in synovial fluid and serum samples, with a focus on those of potential benefit to the equine industry.



Structure and Metabolism of Articular Cartilage and Bone in Health and Disease


Articular cartilage is a complex tissue with an extensive extracellular matrix. The two main components that define the cartilage matrix are type II collagen and aggrecan (see Chapter 61). A balance of synthesis and degradation orchestrated by the chondrocytes maintains normal populations of these molecules within the cartilage matrix. Osteocytes, osteoblasts, and osteoclasts maintain the structural and functional integrity of bone matrix by regulating synthetic and degradative pathways. Synoviocytes also influence homeostasis in cartilage and bone. OA often is characterized by degradative changes within articular cartilage, bone, and synovium. Direct and indirect factors assault the matrix molecules of these tissues, resulting in degeneration and loss of some macromolecules.


What are direct and indirect molecular markers? Direct molecular markers specifically identify a known molecular process within a given tissue. For example, fibrillar collagens, such as types I and II, are synthesized as immature procollagens that undergo proteolytic changes before conversion to mature collagen fibrils. Peptides at either end of the procollagen molecule are cleaved before the procollagen is incorporated into a mature collagen fibril. Estimations of type II collagen synthesis were obtained from synovial fluid and serum samples by using a specific antibody that recognizes the propeptides cleaved from the carboxyl termini.1 Conversely, an indirect molecular marker reflects more general change that is not clearly definable and may represent contributions from several events and tissues. Indirect markers are cytokines, growth factors, and matrix metalloproteinases (MMPs). OA involves changes in subchondral bone and synovium; therefore assessment of molecular markers from these tissues is relevant.



Individual Skeletal Biomarkers of Articular Cartilage Metabolism in Osteoarthritis



Anabolic Processes


The carboxyl propeptide of type II collagen is a useful measure of the anabolic process of type II collagen synthesis. Studies have shown that levels of carboxyl propeptide of type II collagen were significantly higher in synovial fluid from people with OA compared with those without OA. Levels peaked early in the radiological progression of the disease and declined in patients with severe radiological changes.2,3 This biomarker also has been shown to change significantly in serum samples from people with OA and rheumatoid arthritis.4,5


Chondroitin sulfate (CS) is a major glycosaminoglycan (GAG) of aggrecan, and measuring specific CS epitopes on newly synthesized proteoglycan (PG) molecules is a useful biomarker for aggrecan synthesis. An epitope called CS-846 that normally is found in fetal tissues, but is almost absent in healthy adult articular cartilage, has been measured in many species. Levels of CS-846 epitope were increased in synovial fluid in people after injury or primary OA compared with levels in synovial fluid from normal joints. Serum levels were elevated in joint disease but to a lesser extent than synovial fluid levels.6,7 Other CS epitopes such as 3B3 and 7D4 were shown to be useful in assessing cartilage injury in animal models and in people with clinical disease.8 Using arthroscopic evaluation, a negative correlation was found between synovial fluid 3B3 concentrations and gross articular damage that was thought to be caused by decreased normal cartilage volume, or inhibition of synthesis, with increasingly severe lesions. Conversely, in people, increased levels of synovial 7D4 epitope were found in diseased knees compared with contralateral normal knees.9



Catabolic Processes

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Jun 4, 2016 | Posted by in EQUINE MEDICINE | Comments Off on Markers of Osteoarthritis: Implications for Early Diagnosis and Monitoring of the Pathological Course and Effects of Therapy

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