Osteoarthritis as a disease of the cartilage pericellular matrix
Introduction
Under normal physiologic circumstances, articular cartilage functions as a nearly frictionless surface while exposed to loads of several times body weight. This remarkable function is attributed to the unique structure and composition that determine the mechanical properties of the cartilage extracellular matrix (ECM). The ECM of articular cartilage is primarily water (60–85% by wet weight). The remaining solid matrix is composed of a crosslinked network of type II collagen (15–22% by wet weight), proteoglycans (4–7% by wet weight), and lesser amounts of several important other collagens (e.g., VI, IX, X, XI) and non-collagenous proteins [1,2]. The constituents of articular cartilage are organized in a complex porous and permeable ECM that provides the unique capabilities for fluid-pressurization that allow for the long-term load-bearing capabilities of the joint. Under pathologic conditions, such as osteoarthritis, however, the ECM exhibits a myriad of changes in its mechanical function that are associated with increased catabolic activity and inflammation in the joint. In this regard, the role of the ECM in osteoarthritis has been extensively studied and reported in several previous reviews [[3], [4], [5], [6], [7], [8]].
Section snippets
The chondron: the chondrocyte and its pericellular matrix
Alterations in the ECM with osteoarthritis appear to be driven by an imbalance of anabolic and catabolic activities of the chondrocytes, the cell population within articular cartilage. Within the cartilage ECM, chondrocytes are surrounded by a narrow matrix region that is compositionally and structurally distinct from surrounding bulk ECM. This unique region is approximately 2 to 4 μm thick and is called the “pericellular matrix” (PCM) (Fig. 1). The PCM then integrates with the surrounding
The function of the PCM and chondron
Significant evidence is now accumulating on the important role of the PCM (and chondron) in regulating the function of the chondrocyte (reviewed in [18,19]). As every chondrocyte is surrounded by this tissue region, any chemical or physical signals that the chondrocyte perceives may be modulated by the PCM. Although the complete role of the PCM remains to be elucidated, it is apparent that the PCM can serve as a transducer, or “filter,” of both biomechanical and biochemical signals for the
The mechanical properties of the pericellular matrix
Over the past two decades, a variety of techniques have been pioneered to quantify the biomechanical and physical properties of the PCM, using either mechanically or enzymatically isolated chondrons, or in situ testing methods that combine experimental microscopy and computational modeling (reviewed in [18]). For example, physically extracted chondrons have been tested using osmotic swelling [25,34], deformation within hydrogels [33,34,50], or individual chondron testing using compression [[51]
The PCM in osteoarthritis
In healthy articular cartilage, the ECM is maintained in a slow, continuous state of turnover – often described as “homeostasis” – a balance of overall anabolic and catabolic activities of matrix synthesis and degradation. These activities are tightly controlled by the environmental signals (including both biochemical and biomechanical cues) through regulating genetic and epigenetic programming of the chondrocytes. As a transitional zone between the interterritorial matrix and chondrocytes, the
Conclusions
While the role of the cartilage ECM in osteoarthritis has been extensively studied, growing evidence suggests that many of the characteristics and influences of osteoarthritis are present – and possibly initiated – in the PCM. As the primary connection between the chondrocyte and the cartilage ECM, newly synthesized matrix components, enzymes, and growth factors will initially pass through the PCM. Furthermore, the important role that the PCM plays in modulating environmental signals makes it
Acknowledgments
This work was supported in part by the Arthritis Foundation (Arthritis Investigator Award #6462), the Nancy Taylor Foundation for Chronic Diseases, the National Science Foundation (EAGER Award #1638442), Dutch Arthritis Association (DAA_10_1-402, DAF-16-1-405, DAF-15-4-401), the Dutch Scientific Research Council (Grant 91816631/528), and National Institutes of Health grants (AG15768, AR48182, AR50245, AR48852, AG46927, T32 DK108742, T32 EB018266, and P30 AR057235).
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