Joints, and more particularly cartilage and subchondral bone tissues, are always exposed to mechanical stresses.
As outlined in , different stresses can be applied to a tissue, such as:
Different mechanical stresses applied on cartilage.
- - Mechanical stress of compression (loading)
- - Shear stress
- - Tensile stress (stretching)
- - Hydrostatic pressure
When standing, a load of around 0.7 MPa is applied to joints. When walking, a load ranging between 5 and 10 MPa is applied to cartilage [1
] and when doing exercise, a load of over 18 MPa is applied on cartilage [2
]. Numerous in vitro studies show that ExtraCellular Matrix (ECM) production by chondrocytes is highly sensitive to a variety of mechanical signals mediated by loading. Moderate exercise is beneficial for cartilage constitution [3
], while excessive stresses or static stress, disrupt the homeostasis of anabolism and catabolism within cartilage [4
]. The chondrocytes heterogeneity has to be taken into account as well [5
The transmission of mechanical constraints to the cell could be described in four parts:
- - Mechanical coupling which transforms the applied force into different signals to the cell.
- - Mechano-signal transduction through sensitive mechano-receptors such as integrins (such as α5β1-integrin), the stretch-activated ion channels and the cytoskeleton. The chondrocyte cilia seems as well to be a mechanoreceptor as shown by Guilak and collaborators.
- - Signal transduction which converts the mechanical signal into a biochemical signal in the cell, translocating to the nucleus.
- - Cellular response: regulation of gene expression and release of paracrine–autocrine factors.
Different mechanical stresses have been studied in cartilage, in different animal or human models. Biomechanical signals are perceived by cartilage in magnitude-, frequency-, and time-dependent manners. Compression is generally associated with shear stress. Force intensity, frequency and nature of the sample are variable parameters in the different models studied. As a result, it is extremely difficult to compare the different results published in the literature.
Static loading, which has been mainly studied by Grodzinsky, Agarwal and Sharma, has been shown to inhibit matrix synthesis and induce pro-inflammatory genes [6
]. Grodzinsky has recently shown that the inducing of degradative enzymes (MMP-13, ADAMTS-5) by a 50% static loading requires activation of p38 and ERK1/2 MAPKinases [9
]. Sharma and collaborators have evidenced that static load has a degenerative effect in cartilage [8
]. The fluid flow, which is associated with static loading, concentrates cations in the ECM and raises its osmolarity. Cyclic loading elicits a hyper-polarisation through the activation of Ca2+
] and can exert a pro-inflammatory role as shown by Guilak on bovine articular cartilage explants [11
]. Chowdhury et al have used a 3D culture system of chondrocytes in agarose subsequently exposed to a cyclic compression, which thereby counteracts the effects of IL1β on iNOS and COX-2 activity [12
]. Using newborn mouse rib cartilage explants Berenbaum et al have shown that mPGES-1, the last enzymatic step for PGE2
release, is a mechanosensitive gene [13
]. Moreover, they have shown that NF-κB, ERK1/2 and p38 pathways are strongly activated by the mechanical stress of compression on cartilage. These signaling events, lead to the expression of the pro-inflammatory genes MMP-3, MMP-13 and PGE2
]. These results complete previous studies demonstrating that shear stress activates NF-κB, ERK1/2 and p38 pathways. Dynamic biomechanical signals of low-physiologic magnitudes studied by Agarwal, are potent anti-inflammatory signals that inhibit interleukin-1beta-induced pro-inflammatory gene expression and abrogate IL-1beta/tumor necrosis factor-alpha-induced inhibition of matrix synthesis [15
]. Hydrostatic pressure also modulates matrix synthesis. Long term application of hydrostatic pressure greater than 20 MPa suppresses matrix synthesis.
Stretch and shear have been mainly studied by Agarwal, Guilak and Grodzinsky [17
] using aspiration of the chondrocyte membrane with a micro-pipetus for example, and by Millward Sadler and Salter using a model of cyclic shear stress of human monolayer cell culture [20
]. Cell monolayer cultures could only be studied with stretch or shear stress. They have shown that moderate levels of tensile stress act as a protective signal by decreasing the expression of catabolic mediators. A shear stress on bovine explants submitted to cyclic loading shows induction of the MAP ERK1/2 and p38 pathways [9
Some teams have tried to modulate in vivo pressure on cartilage inside the joint by using a taping approach in order to treat lower limb OA focused on the knee. Recently, Richette and collaborators have reviewed data showing a lack of efficacy of this method in vivo [23
The response of cartilage to load will also depend on the quality of subchondral bone.