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. Author manuscript; available in PMC: 2016 Jul 17.
Published in final edited form as: Curr Opin Clin Nutr Metab Care. 2003 May;6(3):289–293. doi: 10.1097/01.mco.0000068964.34812.2b

Signal transduction by mechanical strain in chondrocytes

James Deschner 1, Cynthia R Hofman 1, Nicholas P Piesco 1, Sudha Agarwal 1
PMCID: PMC4947461  NIHMSID: NIHMS801987  PMID: 12690261

Abstract

Purpose of review

Exercise and passive motion exert reparative effects on inflamed joints, whereas excessive mechanical forces initiate cartilage destruction as observed in osteoarthritis. However, the intracellular mechanisms that convert mechanical signals into biochemical events responsible for cartilage destruction and repair remain paradoxical. This review summarizes how signals generated by mechanical stress may initiate repair or destruction of cartilage.

Recent findings

Mechanical strain of low magnitude inhibits inflammation by suppressing IL-1β and TNF-α-induced transcription of multiple proinflammatory mediators involved in cartilage degradation. This also results in the upregulation of proteoglycan and collagen synthesis that is drastically inhibited in inflamed joints. On the contrary, mechanical strain of high magnitude is proinflammatory and initiates cartilage destruction while inhibiting matrix synthesis. Investigations reveal that mechanical signals exploit nuclear factor-kappa B as a common pathway for transcriptional inhibition/activation of proinflammatory genes to control catabolic processes in chondrocytes. Mechanical strain of low magnitude prevents nuclear translocation of nuclear factor kappa B, resulting in the suppression of proinflammatory gene expression, whereas mechanical strain of high magnitude induces transactivation of nuclear factor kappa B, and thus proinflammatory gene induction.

Summary

The beneficial effects of physiological levels of mechanical signals or exercise may be explained by their ability to suppress the signal transduction pathways of proinflammatory/catabolic mediators, while stimulating anabolic pathways. Whether these anabolic signals are a consequence of the inhibition of nuclear factor kappa B or are mediated via distinct anabolic pathways is yet to be elucidated.

Keywords: cartilage, chondrocytes, inflammation, mechanical strain, signal transduction

Introduction

Articular cartilage is an avascular tissue made up of chondrocytes anchored in a highly structured matrix, consisting of proteoglycans, type II and other minor collagens, and non-collagenous proteins. Type II collagen provides the structural tensile strength and stiffness of the cartilage framework, whereas hydrodynamically active large aggregating and smaller non-aggregating proteoglycans provide compressive strength [1]. Chondrocytes bind to the cartilage matrix via integrins, CD44, and collagen and hyaluran receptors [2,3••,4]. Mechanical signals generated during physiological loading are perceived by these receptors and are transmitted to the intracellular compartment for homeostatic regulation and functional integrity of chondrocytes.

The surrounding environment profoundly influences the synthetic functions of articular chondrocytes. After acute traumatic loading or exposure to inflammatory insults, activated chondrocytes and cells of the synovium drive biochemical events that lead to the synthesis of proinflammatory mediators known to be destructive to joints [5]. IL-1β and TNF-α are prominent mediators of cartilage destruction [5–7,8••], and both can activate chondrocytes and synovial cells to produce IL-1β, TNF-α, IL-8, IL-18, and IL-6, as well as matrix metalloproteinases (MMPs), nitric oxide, and prostaglandin E2. Proinflammatory mediators also induce apoptosis and inhibit anabolic pathways, i.e. the synthesis of proteoglycans, collagen type-II, and tissue inhibitors of metalloproteinases (TIMPs). The induction of proinflammatory genes and their corresponding gene products, as well as the inhibition of matrix synthesis thus set up a self-sustaining inflammatory loop that exacerbates cartilage destruction [9–17].

Biomechanical loading in cartilage repair and destruction

The facts that: (1) immobilization is associated with a decrease in total glycosaminoglycans [18,19]; (2) mechanical forces applied during moderate exercise or continuous passive motion limit cartilage degradation and augment cartilage repair in inflamed and post-surgical joints [20–22]; and (3) traumatic or excessive loading may lead to cartilage breakdown and osteoarthritic lesions [23–25], indicate that biomechanical loading is important in cartilage homeostasis, repair, as well as destruction.

During joint movement, cartilage matrix is exposed to complex interstitial tensile, compressive, and shear stresses [26]. Because of close connections between the pericellular matrix and chondrocytes, these cells also experience tension, compression, and shear even under simple compressive loading conditions [27–31]. In-vivo and in-vitro studies [32–34,35•] have suggested that the type (compression, tension, shear), frequency, duration, and magnitude of mechanical force all affect cellular responses and are important determinants of the ultimate fate of the articular cartilage. For example, static compressive strain not only exerts proinflammatory and catabolic effects [33–34,35•,36], it also inhibits anabolic responses to growth factors [37]. However, dynamic compression as well as tension at appropriate magnitude and frequency induce anti-inflammatory [30,38••] and anabolic responses [38••,39–41], as well as supporting the effects of growth factors on chondrocytes [42•,43].

Inflammatory pathways provide a key to understanding biomechanical signaling

The modulation of proinflammatory pathways appears to be central to the actions of signals generated by mechanical stress, i.e. excessive loading initiates inflammatory pathways, whereas therapeutic loading of diseased joints frequently results in the suppression of inflammation [1,2,4,20–22]. Similar anti-inflammatory effects of dynamic tensile and compressive forces of low physiological magnitudes are observed, in vitro. Cyclic tensile strain of low magnitude (TENS-L; 3–8% equibiaxial strain) acts as a potent antagonist of IL-1β and TNF-α actions, i.e. it inhibits the IL-1-induced expression of multiple proinflammatory genes. These gene products include inducible nitric oxide synthase, cyclooxygenase, and MMP-1, MMP-3, MMP-9 and MMP-13. The downregulation of these catabolic proteins by TENS-L results in the inhibition of nitric oxide and prostaglandin E2 production as well as matrix degradation [40,41,44•,45] (Long P, Verma A, Hofman C, et al., 2003, in preparation).

Similar to tensile strain, signals generated by physiological levels of cyclic compressive forces (15% compression) are also anti-inflammatory and inhibit IL-1β-induced prostaglandin E2 and nitric oxide production in chondrocytes [30,31]. Interestingly, tensile or compressive forces of higher magnitudes induce the synthesis of proinflammatory mediators such as nitric oxide and prostaglandin E2, and may thus exacerbate the effects of IL-1β and TNF-α [36] (Long P, Verma A, Hofman C, et al., 2003, in preparation). The findings suggest that mechanical signals act on cells in a magnitude-dependent manner. Furthermore, mechanical signals of high and low magnitudes act on the proinflammatory signal transduction cascade upstream of messenger RNA transcription.

Anti-inflammatory and proinflammatory signals generated by mechanical strain are coupled to synthetic pathways

The effects of mechanical signals on joints are paralleled by the modulation of matrix synthesis, i.e. physiological loading of inflamed joints stimulates matrix synthesis, whereas excessive loading leads to the inhibition of matrix synthesis [21,22]. Chondrocytes exhibit a similar phenomenon in vitro. For example, in parallel to the inhibition of proinflammatory gene induction, TENS-L upregulates mRNA synthesis for matrix-associated proteins that are inhibited by IL-1β. These matrix constituents include sulfated glycosaminoglycans, aggrecan, and collagen type II, all of which are involved in cartilage synthesis [41,42•,44•,45]. Exposure of chondrocytes to TENS-L also results in the reversal of the IL-1β-mediated inhibition of TIMP-II mRNA expression and synthesis. As TIMP-II inhibits the actions of MMPs, the enhanced synthesis of TIMP-II may be yet another way in which TENS-L limits cartilage degradation by MMPs [41,42•,44•,45]. The mechanical signals generated by TENS-L thus act in an integrated manner. These signals inhibit the synthesis of catabolic proteins and upregulate the synthesis of extracellular matrix. Interestingly, an inflammatory signal is a prerequisite for such actions, because TENS-L itself fails to evoke matrix synthesis. Similar to tensile forces, signals generated by physiological levels of dynamic compressive force are also anabolic [33,37,38••,39–41,42•,44•]. These signals induce glycosaminoglycan and aggrecan synthesis, support the effects of insulin-like growth factor, as well as promote proliferation and proteoglycan synthesis in cartilage explants [37,38••,39]. On the other hand, static compressive loading is catabolic, in that it inhibits the effects of insulin-like growth factor, and decreases aggrecan and glycosaminoglycan synthesis in cartilage explants [23–25]. These findings suggest that matrix synthesis is regulated, not only by the magnitude, but also by the frequency of biomechanical signals.

Signals generated by dynamic cyclic tensile strain of high magnitude (TENS-H; 10–15% equibiaxial strain) inhibit proteoglycan and collagen type-II synthesis in vitro. Similarly, signals generated by dynamic and static compressive forces inhibit proteoglycan synthesis. This is similar to what is observed in vivo when vigorous impact exercise exacerbates cartilage degradation and induces osteoarthritis [23–25]. The chondrocytic anti-inflammatory and proinflammatory responses to mechanical signals are thus coupled to the synthesis of anabolic proteins. Anti-inflammatory signals are coupled to the augmentation of matrix synthesis, whereas proinflammatory signals are coupled to the inhibition of matrix synthesis.

Biomechanical signals utilize proinflammatory pathways for their pro and anti-inflammatory actions

It is widely accepted that cell surface receptors, such as integrins, cell adhesion molecules, and ion-activated channels trigger mechanically induced signal transduction [2,3• •,4]. Chondrocytes use β1 integrin mechano-receptors for transducing extracellular mechanical signals into intracellular biochemical effects. Integrins are cell surface adhesion receptors that link the extracellular matrix and cell surface ligands to the cytoplasmic actin cytoskeleton. After stimulation and clustering, integrins can activate, by tyrosine phosphorylation, several cytoskeleton-associated proteins at focal adhesion sites, such as paxillin, talin, vinculin, tensin, focal adhesion kinase and the src family of protein tyrosine kinases. Focal adhesion kinase is considered to be an important link between integrin receptors and the activation of downstream targets such as extracellular signal-related kinase and c-jun N-terminal kinase. These molecules in turn are believed to activate nuclear transcription factors such as nuclear factor kappa B (NF-κB) and activator protein-1 [2,3••,4].

In view of the fact that TENS-L suppresses the proinflammatory actions of IL-1β and TNF-α, the possibility of the down-regulation of IL-1β/TNF-α receptors by TENS-L has been examined. Functional studies of chondrocytes showed that cells subjected to TENS-L retained IL-1β responsiveness. This suggests that mechanical signals do not down-regulate IL-1β/TNF-α receptors significantly [40,41,44•]. Therefore, the actions of TENS appear to be mediated by the inhibition of key step(s) in the signal transduction cascade of IL-1β. The NF-κB signal transduction pathway is central to proinflammatory gene induction. NF-κB, a ubiquitously expressed transcription factor, plays an established role in the cytosolic signalling of proinflammatory cytokines. It exists as a heterogeneous collection of dimers formed by various combinations of members of the NF-κB/Rel protein family. In resting cells, NF-κB is sequestered in an inactive cytoplasmic form via interactions with the inhibitory protein, inhibitor of nuclear factor kappa B (I-κB). Cell stimulation by molecules such as IL-1β or TNF-α results in rapid phosphorylation and degradation of I-κB. Degradation of I-κB releases NF-κB, which then translocates to the nucleus, binds to specific consensus sequences, and activates a plethora of proinflammatory genes [46].

An examination of the actions of mechanical signals on the NF-κB pathway has shown that TENS-L inhibits the IL-1β-induced nuclear translocation of NF-κB within 15 min, and this inhibition is sustained for several hours. TENS-L inhibits IL-1β-induced nuclear translocation of the p65/p50 dimers of NF-κB, suggesting that TENS-L signals may specifically act on pathways activated by IL-1β. TENS-L inhibits the dissociation of NF-κB from cytosolic complexes with I-κBβ, and thus prevents its entry into the nucleus.

In contrast to TENS-L, TENS-H is a potent proinflammatory signal, and it is thus not surprising that its actions are mediated by NF-κB transactivation (unpublished observations). Furthermore, TENS-H induces I-κBβ degradation and the nuclear translocation of p65 and p50 heterodimers of NF-κB, suggesting that TENS-H induces proinflammatory signals similar to those induced by proinflammatory cytokines. Despite being a physical signal, TENS-H thus acts in a manner similar to molecular activators that stimulate the transcriptional activity of NF-κB.

Unfortunately, the intracellular actions of compressive and shear forces have yet to be delineated. As the gene activation studies show that signals generated by compressive forces induce anti-inflammatory and proinflammatory gene induction similar to tensile forces, it would not be surprising to find that these signals activate pathways similar to tensile forces.

Conclusion

Regular exercise is known to be essential for avoiding the onset of arthritic diseases, and therapeutic exercise is known to be a critically important component in limiting the progression of these diseases. However, mechanistic studies fail to explain the molecular basis for the success or failure of exercise-based therapies in arthritic patients. In general, it is believed that increased blood flow induced by motion disseminates the inflammatory exudates from synovial joints to lessen their destructive effects. Recent findings revealed that cells of the cartilage are the direct targets of mechanical signals, and that mechanical signals are potent modulators of the synthetic responses of chondrocytic cells. Chondrocytes can recognize the type of mechanical signals, their magnitude, and their frequency, and respond to them differently. Low/physiological levels of tensile and compressive strains are anti-inflammatory and activate anabolic pathways, whereas excessive loading is proinflammatory and initiates cartilage damage. Although little is known about the signal transduction pathways of compressive forces, it appears that the NF-κB pathway is central to the actions of signals generated by tensile strain (Figure 1). Low or physiological levels of TENS-L generate signals that inhibit NF-κB transactivation to limit the inflammation triggered by IL-1β and TNF-α. In contrast, TENS-H generates signals that employ NF-κB to initiate proinflammatory gene transcription and to induce tissue destruction. TENS-L also induces anabolic signals, i.e. the synthesis of matrix-associated proteins, i.e. proteoglycans, collagen type-II, and TIMP-II, despite the presence of IL-1β or TNF-α [6,7,17,18]. Whether these anabolic actions of TENS-L are a consequence of the inhibition of NF-κB-activated catabolic gene induction or are mediated via distinct anabolic pathways is as yet unknown. On the other hand, TENS-H itself is catabolic and inhibits anabolic gene expression [1,9,11,12]. It has yet to be revealed whether the catabolic actions of TENS-H involve the activation of signal transduction pathways other than NF-κB. A further understanding of the molecular mechanisms that mediate the anti-inflammatory and reparative actions of mechanical strain will provide us with defined parameters needed for the safe application of motion-based therapies to restrict cartilage destruction and augment repair in arthritic joints.

Figure 1. Mechanical signals of low and high magnitude regulate chondrocytic responses by utilizing the NF-κB pathway.

Figure 1

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Mechanical signals of low magnitude suppress IL-1β-induced NF-κB nuclear translocation via inhibition of I-κB degradation. Failure of NF-κB transactivation results in the suppression of proinflammatory gene induction. This is accompanied by an increase in matrix synthesis. In contrast, mechanical signals of high magnitude act similar to IL-1 and augment proinflammatory gene induction by stimulating I-κB degradation and NF-κB nuclear translocation. Simultaneously, these signals inhibit matrix synthesis. I-κB, Inhibitor of nuclear factor kappa B; NF-κB, nuclear factor kappa B, TENS-H, cyclic tensile strain of high-magnitude; TENS-L, cyclic tensile strain of low-magnitude.

Acknowledgments

This work was supported by grants AT00646, HD40939, and AR48781 from the National Institutes of Health, Bethesda, MD, USA.

Abbreviations

I-κB

inhibitor of nuclear factor kappa B

MMP

matrix metalloproteinase

NF-κB

nuclear factor kappa B

TENS-H

high-magnitude cyclic tensile strain

TENS-L

low-magnitude cyclic tensile strain

TIMP

tissue inhibitor of matrix metalloproteinase

References and recommended reading

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