Osteoarthritis as a disease of the cartilage pericellular matrix

Abstract

Osteoarthritis is a painful joint disease characterized by progressive degeneration of the articular cartilage as well as associated changes to the subchondral bone, synovium, and surrounding joint tissues. While the effects of osteoarthritis on the cartilage extracellular matrix (ECM) have been well recognized, it is now becoming apparent that in many cases, the onset of the disease may be initially reflected in the matrix region immediately surrounding the chondrocytes, termed the pericellular matrix (PCM). Growing evidence suggests that the PCM - which along with the enclosed chondrocytes are termed the "chondron" - acts as a critical transducer or "filter" of biochemical and biomechanical signals for the chondrocyte, serving to help regulate the homeostatic balance of chondrocyte metabolic activity in response to environmental signals. Indeed, it appears that alterations in PCM properties and cell-matrix interactions, secondary to genetic, epigenetic, metabolic, or biomechanical stimuli, could in fact serve as initiating or progressive factors for osteoarthritis. Here, we discuss recent advances in the understanding of the role of the PCM, with an emphasis on the reciprocity of changes that occur in this matrix region with disease, as well as how alterations in PCM properties could serve as a driver of ECM-based diseases such as osteoarthritis. Further study of the structure, function, and composition of the PCM in normal and diseased conditions may provide new insights into the understanding of the pathogenesis of osteoarthritis, and presumably new therapeutic approaches for this disease.

Keywords: Aggrecan; Chondrocyte; Chondron; Decorin; Extracellular matrix; Intervertebral disc; Mechanobiology; Mechanotransduction; Meniscus; Osteoarthritis; Perlecan; Territorial matrix; Type VI collagen.

Figure 1. Schematic of the chondrocyte, which together with its surrounding pericellular matrix (PCM) forms a chondron, embedded within the cartilage ECM

The PCM is rich in proteoglycans such as perlecan and is characterized by the presence of collagens type VI and IX, as well as several other matrix macromolecules (fibronectin, laminin, etc.). Because the PCM surrounds the chondrocyte, it is believed to serve as a transducer, or “filter”, of the biomechanical milieu through regulation of the stress-strain, osmotic, and fluid-flow environments of the chondrocyte. In addition to this mechanobiologic role, the PCM can regulate cell-ECM ligand binding, growth factor and enzyme sequestration, transport, assembly, and activation, thus influencing major aspects of ECM turnover in cartilage

Figure 2. Alterations in the morphology and mechanical properties of the PCM with osteoarthritis

(A, B) Representative images of immunofluorescence labeling of type VI collagen in cartilage from (A) macroscopically normal and (B) osteoarthritic knee joints. Scale bar = 100 μm (C, D) Immunofluorescence labeling revealed altered structure and expanded regions that were positive for type VI collagen in the PCM of osteoarthritic cartilage. Scale bar = 25 μm. (E, F) Elastic mapping of the moduli of the ECM and PCM, from normal (E) and osteoarthritic (F) cartilage, showing a loss of mechanical properties with osteoarthritis. Modulus maps are presented on the same graded coloring scale, and cell-sized voids are depicted in white [Adapted from [65], with permission].