Osteoarthritis
New Insights into the Pathobiology of Cartilage Degeneration— Implications for Therapeutic Interventions in Osteoarthritis
Emily A LeBlanc, BSc1 and Frank Beier, PhD2 1. MSc Student, 2. Associate Professor, Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario
Abstract
Articular cartilage degeneration is a hallmark of osteoarthritis (OA). Specifically, the excessive breakdown of the extracellular matrix (ECM) in cartilage tissue contributes to the development of OA. However, the molecular events that contribute to this breakdown remain partially unknown. Recent research in this field aims to determine the catabolic factors that are important in cartilage, with the overall goal of developing effective treatment options. Matrix metallopeptidase (MMP)-13 and a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS)-4/5 have been found to be the main enzymatic contributors to ECM breakdown. In addition, hypoxia-inducible factor (HIF)-2α has been newly implied as having a catabolic role in cartilage. Here, we review recent findings and advances in the understanding of these catabolic factors, with a focus on their therapeutic implications. We also consider possible future advances in these areas of research.
Keywords Osteoarthritis, cartilage, chondrocytes, MMP13, ADAMTS-4, ADAMTS-5, hypoxia-inducible factors
Disclosure: The authors have no conflicts of interest to declare. Acknowledgment: The authors thank Matthew McCann for help with the figures. Emily A LeBlanc, BSc, is supported by the Joint Motion Program (JuMP), a Canadian Institutes for Health Research (CIHR) training program in musculoskeletal health research and leadership. Work in the laboratory of Frank Beier, PhD, is supported by grants from the CIHR and a Canada Research Chair award. Received: January 25, 2011 Accepted: March 10, 2011 Citation: US Musculoskeletal Review, 2011;6(1):16–9 Correspondence: Frank Beier, PhD, Dental Sciences Building, Room 0035B, Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, N6A 5C1, Canada. E:
fbeier@uwo.ca
Osteoarthritis (OA) is the most common musculoskeletal disorder, affecting a large proportion of the aging population.1,2
OA is a
degenerative joint disease that involves the extensive and premature breakdown of articular cartilage in joint structures throughout the body.3 With the degeneration of articular cartilage, chronic pain and impaired joint function arise as the main symptoms of the disease.4
Despite its
prevalence, the underlying molecular mechanisms of OA are not well understood and, as a result, no cure or long-term treatment plan has been effectively established. Current treatment options are restricted to management of the disease symptoms and do not address the underlying changes in cartilage biology. Current research in this field focuses on determining the molecular events in cartilage that eventually contribute to the breakdown of this tissue and its extracellular matrix (ECM). The overall research goal is to establish either effective preventive measures or an effective treatment option.
At the structural level, cartilage has a large amount of ECM (Figure 1), consisting largely of a collagen fibril network, mainly type II collagen, and proteoglycan molecules, the most abundant being aggrecan.5–7
In
healthy cartilage, a balance exists between matrix synthesis and degradation. However, during the disease state of OA, this equilibrium is shifted in favor of matrix degradation.8,9
16 Investigation into the catabolic
factors responsible for the breakdown of cartilage tissue is a promising approach in the search for an effective treatment option for OA. Intensive research efforts have focused on determining the molecular mechanisms responsible for degrading each of the ECM components, with the proteases matrix metallopeptidase (MMP)-13 and a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS)-4/5 emerging as major catabolic contributors to the breakdown of cartilage ECM. Additional factors, including hypoxia-inducible factor (HIF)-2α, have been implied more recently as having a regulatory role in cartilage cell (chondrocyte) physiology in general and in the breakdown of cartilage tissue in particular. Here, we provide an overview of current findings, as well as of the present understanding of the events that contribute to the development of OA. Our focus is on selected catabolic factors of cartilage tissue, specifically MMP13 and ADAMTS-4/5, and the regulatory factor HIF-2α.
MMP13 in Osteoarthritis
MMP13, also referred to as collagenase-3, is the main enzymatic contributor to collagen breakdown in the cartilage matrix and preferentially cleaves the major collagen species in articular cartilage, type II collagen.10,11
Although MMP13 is mainly involved in the cleavage of the collagen network of cartilage, it also contributes to the
© TOUCH BRIEFINGS 2011
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