**1. Introduction**

The temporomandibular joint (TMJ) is a unique joint, consisting of a fossa, disc, and condyle that is essential for mastication, speech, and deglutition [1]. The major difference between the TMJ and other synovial joints is that the TMJ contains fibrocartilage rather than hyaline cartilage, i.e., it contains collagen type I in addition to collagen type II and proteoglycans [2]. More precisely, the matrix of all three anatomical structures of the TMJ contained collagen type I. The condyle and the fossa stained positive for collagen type II and proteoglycans, but the condyle contained considerably more collagen type II and proteoglycans than the fossa. The disc did not contain collagen type II, and the disc did not stain positive for proteoglycans [2]. The TMJ is an under-recognized joint in arthritic disease, while it is one of the most commonly affected joints in patients with juvenile idiopathic arthritis (JIA) [3]. It has been suggested that at the time of diagnosis, approximately 75% of JIA patients have problems with the TMJ [3]. JIA, the most prevalent type of arthritis of unknown cause in young children, is initiated before the age of 16 years old and is characterized by chronic inflammation of the joints, which can result in joint degradation. Affected children suffer from jaw pain but also jaw dysfunction, which can manifest in malocclusion [4] and a reduced maximum mouth opening [5]. How the cartilage of the TMJ is affected by inflammation in JIA and in other arthritic diseases with involvement of the TMJ remains elusive.

One of the most potent inflammatory factors involved in hyaline cartilage degradation in many forms of arthritis is interleukin (IL)-1β [6]. This cytokine is responsible for hyaline cartilage matrix degradation by inducing expression of matrix metalloproteinases (MMPs) and disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) by chondrocytes [7,8]. The importance of IL-1β in the pathogenesis of systemic arthritic diseases is demonstrated by the success of treatment with IL-1 receptor antagonist (IL-1RA) [9]. However, it is unknown whether IL-1β also affects the integrity of the cartilaginous structures of the TMJ.

Since the TMJ is a secondary growth center, damage induced by catabolic factors during JIA can introduce growth abnormalities, resulting in asymmetric growth of the mandible [10] undersized jaw, and abnormal positioning of the maxilla [11]. Therefore, strategies to prevent TMJ joint damage, particularly in JIA patients, are highly desirable. Preferably, a non-invasive treatment should be deployed that inhibits the catabolic effect of inflammatory factors on TMJ cartilage. Mechanical loading of inflamed joints can be a promising approach towards achieving this. Moderate exercise has been shown to have a systematic anti-inflammatory effect by reducing the disease activity in rheumatoid arthritis (RA) patients [12]. Furthermore, mechanical loading reduced the expression of MMP-13 in synovial cells from RA patients [13]. However, it is not known whether mechanical loading will also reduce IL-1β-induced expression of catabolic factors in cells derived from the TMJ condyle, which is especially susceptible to damage in JIA [14].

We hypothesize that IL-1β plays an important role in inducing degradation of the TMJ cartilage, that it enhances expression of catabolic factors such as MMPs and ADAMTSs, and that mechanical stimuli can revert IL-1β-induced expression of catabolic factors. We have used different model systems to investigate this hypothesis. First of all, an IL1RA knock-out mouse model was used to investigate whether overactive IL-1β signaling induces histological signs of damage in the fibrocartilage tissue of the temporomandibular joint. The second and third part of the hypothesis was challenged using pig TMJ-derived cells. Pigs were chosen to isolate cells because they will yield more cells than mice and because the TMJ of this species is comparable with that of humans in cellular composition [15–19].
