Elsevier

Matrix Biology

Volumes 71–72, October 2018, Pages 40-50
Matrix Biology

Osteoarthritis as a disease of the cartilage pericellular matrix

https://doi.org/10.1016/j.matbio.2018.05.008Get rights and content

Highlights

  • The PCM surrounds all chondrocytes in articular cartilage and regulates their interactions with the environment.

  • Alterations in PCM properties and composition will influence the chondrocyte's mechanobiologic response to loading.

  • Some of the earliest biosynthetic and degradative changes in osteoarthritis may initially manifest in the PCM.

  • Here we review the potential role of PCM pathology as a potential driver, as well as indicator, of osteoarthritis.

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.

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).

References (128)

  • M.M. Knight et al.

    The influence of elaborated pericellular matrix on the deformation of isolated articular chondrocytes cultured in agarose

    Biochim. Biophys. Acta

    (1998)
  • W.A. Hing et al.

    The influence of the pericellular microenvironment on the chondrocyte response to osmotic challenge

    Osteoarthr. Cartil.

    (2002)
  • J.B. Choi et al.

    Zonal changes in the three-dimensional morphology of the chondron under compression: the relationship among cellular, pericellular, and extracellular deformation in articular cartilage

    J. Biomech.

    (2007)
  • T.L. Vincent

    Targeting mechanotransduction pathways in osteoarthritis: a focus on the pericellular matrix

    Curr. Opin. Pharmacol.

    (2013)
  • L. Xu et al.

    Intact pericellular matrix of articular cartilage is required for unactivated discoidin domain receptor 2 in the mouse model

    Am. J. Pathol.

    (2011)
  • Z. Zhang et al.

    Comparison of gene expression profile between human chondrons and chondrocytes: a cDNA microarray study

    Osteoarthr. Cartil.

    (2006)
  • R.A. Andhare et al.

    Hyaluronan promotes the chondrocyte response to BMP-7

    Osteoarthr. Cartil.

    (2009)
  • M.M. Knight et al.

    Chondrocyte deformation within mechanically and enzymatically extracted chondrons compressed in agarose

    Biochim. Biophys. Acta

    (2001)
  • L. Ng et al.

    Nanomechanical properties of individual chondrocytes and their developing growth factor-stimulated pericellular matrix

    J. Biomech.

    (2007)
  • F. Guilak et al.

    The deformation behavior and mechanical properties of chondrocytes in articular cartilage

    Osteoarthr. Cartil.

    (1999)
  • L.G. Alexopoulos et al.

    Osteoarthritic changes in the biphasic mechanical properties of the chondrocyte pericellular matrix in articular cartilage

    J. Biomech.

    (2005)
  • D.M. Allen et al.

    Heterogeneous nanostructural and nanoelastic properties of pericellular and interterritorial matrices of chondrocytes by atomic force microscopy

    J. Struct. Biol.

    (2004)
  • E.M. Darling et al.

    Spatial mapping of the biomechanical properties of the pericellular matrix of articular cartilage measured in situ via atomic force microscopy

    Biophys. J.

    (2010)
  • M.A. McLeod et al.

    Depth-dependent anisotropy of the micromechanical properties of the extracellular and pericellular matrices of articular cartilage evaluated via atomic force microscopy

    J. Biomech.

    (2013)
  • R.E. Wilusz et al.

    A biomechanical role for perlecan in the pericellular matrix of articular cartilage

    Matrix Biol. J. Int. Soc. Matrix Biol.

    (2012)
  • R.E. Wilusz et al.

    Micromechanical mapping of early osteoarthritic changes in the pericellular matrix of human articular cartilage

    Osteoarthr. Cartil.

    (2013)
  • R.E. Wilusz et al.

    High resistance of the mechanical properties of the chondrocyte pericellular matrix to proteoglycan digestion by chondroitinase, aggrecanase, or hyaluronidase

    J. Mech. Behav. Biomed. Mater.

    (2014)
  • C. Prein et al.

    Structural and mechanical properties of the proliferative zone of the developing murine growth plate cartilage assessed by atomic force microscopy

    Matrix Biol. J. Int. Soc. Matrix Biol.

    (2016)
  • E.M. Darling et al.

    Viscoelastic properties of zonal articular chondrocytes measured by atomic force microscopy

    Osteoarthr. Cartil.

    (2006)
  • C.A. Poole et al.

    Immunolocalization of type IX collagen in normal and spontaneously osteoarthritic canine tibial cartilage and isolated chondrons

    Osteoarthr. Cartil.

    (1997)
  • G.M. Lee et al.

    The incidence of enlarged chondrons in normal and osteoarthritic human cartilage and their relative matrix density

    Osteoarthr. Cartil.

    (2000)
  • I. Holloway et al.

    Increased presence of cells with multiple elongated processes in osteoarthritic femoral head cartilage

    Osteoarthr. Cartil.

    (2004)
  • P.G. Bush et al.

    The volume and morphology of chondrocytes within non-degenerate and degenerate human articular cartilage

    Osteoarthr. Cartil.

    (2003)
  • E.H. Mrosek et al.

    Subchondral bone trauma causes cartilage matrix degeneration: an immunohistochemical analysis in a canine model

    Osteoarthr. Cartil.

    (2006)
  • J. Chang et al.

    Sequestration of type VI collagen in the pericellular microenvironment of adult chrondrocytes cultured in agarose

    Osteoarthr. Cartil.

    (1996)
  • M. Arican et al.

    Increased metabolism of collagen VI in canine osteoarthritis

    J. Comp. Pathol.

    (1996)
  • S. Soder et al.

    Ultrastructural localization of type VI collagen in normal adult and osteoarthritic human articular cartilage

    Osteoarthr. Cartil.

    (2002)
  • O. Horikawa et al.

    Distribution of type VI collagen in chondrocyte microenvironment: study of chondrons isolated from human normal and degenerative articular cartilage and cultured chondrocytes

    J. Orthop. Sci. Off. J. Jpn. Orthop. Assoc.

    (2004)
  • R. Ruhlen et al.

    The chondrocyte primary cilium

    Osteoarthr. Cartil.

    (2014)
  • B. Schminke et al.

    Laminins and nidogens in the pericellular matrix of chondrocytes: their role in osteoarthritis and chondrogenic differentiation

    Am. J. Pathol.

    (2016)
  • A.L. Stevens et al.

    Mechanical injury and cytokines cause loss of cartilage integrity and upregulate proteins associated with catabolism, immunity, inflammation, and repair

    Mol. Cell. Proteomics

    (2009)
  • L. Xu et al.

    Activation of the discoidin domain receptor 2 induces expression of matrix metalloproteinase 13 associated with osteoarthritis in mice

    J. Biol. Chem.

    (2005)
  • D.W. Holt et al.

    Osteoarthritis-like changes in the heterozygous sedc mouse associated with the HtrA1-Ddr2-Mmp-13 degradative pathway: a new model of osteoarthritis

    Osteoarthr. Cartil.

    (2012)
  • D. Eyre

    Collagen of articular cartilage

    Arthritis Res.

    (2002)
  • D. Heinegard

    Fell-Muir lecture: proteoglycans and more—from molecules to biology

    Int. J. Exp. Pathol.

    (2009)
  • D.R. Eyre

    Collagens and cartilage matrix homeostasis

    Clin. Orthop. Relat. Res.

    (2004)
  • J. Gouttenoire et al.

    Modulation of collagen synthesis in normal and osteoarthritic cartilage

    Biorheology

    (2004)
  • D. Heinegard et al.

    The role of the cartilage matrix in osteoarthritis

    Nat. Rev. Rheumatol.

    (2011)
  • M. Maldonado et al.

    The role of changes in extracellular matrix of cartilage in the presence of inflammation on the pathology of osteoarthritis

    Biomed. Res. Int.

    (2013)
  • A. Benninghoff

    Form und bau der Gelenkknorpel in ihren Beziehungen Zur Funktion

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