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

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Mechanical joint loading is an essential factor in joint homeostasis but it is also the most important aetiological factor in the development of osteoarthritis (OA). Although OA has long been regarded a disease of ‘wear and tear’, data arising from studies over the past 10 years have put pay to a mechanical ‘attrition’ theory of OA and place the induction and activation of specific matrix degrading enzymes centrally in the disease process. The finding that these enzymes are induced in vivo in a mechanosensitive manner provides a clear and sensible unifying hypothesis for disease pathogenesis; namely that mechanical ‘wear’ actively drives the enzymes that produce ‘tear’. This review focuses on recent advances in our knowledge of the molecular mechanisms by which chondrocytes (and most likely other cells of the joint) sense and respond to changes in their mechanical environment. As mechanical signals drive both beneficial responses as well as those that drive disease, modulation of specific pathways provides a choice of strategies for treating OA.

Highlights

► Mechanical factors are critical for joint homeostasis as well as for the development of OA. ► The pericellular matrix sequesters regulatory factors that are released upon mechanical load. ► Mechanotransduction pathways represent potential targets in OA.

Section snippets

Joint tissues are highly mechanosensitive

Mechanical signals are important homeostatic factors in the joint as well as being critical for the development of OA. Articular cartilage, like bone, rapidly loses volume upon joint immobilization as seen when individuals lose the ability to weight-bear, for instance following acute spinal injury [1]. This has also been demonstrated in experimental models where joint immobilization by casting causes atrophy of cartilage [2], a process that is reversible upon remobilization [3]. The evidence

Mechanosensing through the extracellular matrix

Articular cartilage is a complex tissue in which a relatively small number of cells (occupying approximately 5% of tissue volume) are embedded within a highly structured extracellular matrix (ECM). The matrix is divided into two major components; the further removed matrix, encompassing the territorial and interterritorial matrix, and the pericellular matrix (PCM). The further removed matrix is rich in fibrillar type II collagen and the chondroitin sulphate proteoglycan, aggrecan and is

The pericellular matrix as sensor and effector of mechanical signals

The PCM is a 1–5 μm region immediately surrounding the chondrocyte, and together with the chondrocyte is termed the chondron [21]. It is devoid of type II collagen but rich in the non-fibrillar type VI collagen and the heparan sulphate proteoglycan perlecan [22, 23]. The PCM has long been regarded as having key mechanosensing properties and is thought to be able to amplify mechanical signals transmitted through the ECM (reviewed in [24, 25]). The mechanotransduction properties of the PCM have

Regulatory molecules within the PCM

The PCM is also a repository for a number of growth factors and other regulatory molecules, which may be released in response to mechanical signals. The best described of these is fibroblast growth factor 2 (FGF2) which is sequestered on the heparan sulphate chains of perlecan and is released in response to cutting injury and cyclical compression [28, 29]. Released FGF2 delivers beneficial signals to the chondrocyte, and mice in which the gene for FGF2 has been deleted develop accelerated OA

What controls the bioavailability of pericellular molecules upon mechanical load?

The way in which FGF2 and other regulatory molecules are released from the matrix in response to mechanical signals is not known but a recent paper by Duchesne et al. highlights the dynamic nature of the interaction between FGF2 and the matrix. They tracked the movement of gold-nanoparticle-labelled FGF2 molecules in the pericellular environment of fibroblasts and showed that whilst FGF2 molecules are often confined within the matrix, they also exhibit dynamic translocation, which the authors

The pericellular matrix in osteoarthritis

Whilst degradation of the extracellular matrix is a classical finding in OA, there is no good evidence that the pericellular matrix diminishes in disease. If anything, the volume of this part of the matrix appears expanded. Many of the constituent proteins of the PCM such as perlecan and type VI collagen are increased [22, 57, 58], as well as the regulatory molecules that it holds such as FGF2 and CTGF (Vincent et al., unpublished results). The mechanical properties of the PCM change in

Concluding comments

The pericellular matrix plays a key role in the sequestration and release of molecules in a number of different tissues. Quite how these molecules are released in response to mechanical load is unknown, but their bioavailability is likely to be affected by modification of the matrix, and by a change in the mechanical environment, both of which occur in OA. The chondrocyte's response to mechanical factors can be both ‘good’ (chondroprotective) and ‘bad’ (disease promoting) for the joint, so

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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