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. 2009 Jun;88(6):557–562. doi: 10.1177/0022034509336823

IL-1β Inhibits TGFβ in the Temporomandibular Joint

WH Lim 1, J Toothman 2, JH Miller 2, RH Tallents 2, SM Brouxhon 3,5, ME Olschowka 2, S Kyrkanides 2,4,*
PMCID: PMC3317986  PMID: 19587162

Abstract

Similarly to humans, healthy, wild-type mice develop osteoarthritis, including of the temporomandibular joint (TMJ), as a result of aging. Pro-inflammatory cytokines, such as IL-1β, IL-6, and TNFα, are known to contribute to the development of osteoarthritis, whereas TGFβ has been associated with articular regeneration. We hypothesized that a balance between IL-1β and TGFβ underlies the development of TMJ osteoarthritis, whereby IL-1β signaling down-regulates TGFβ expression as part of disease pathology. Our studies in wild-type mice, as well as the Col1-IL1βXAT mouse model of osteoarthritis, demonstrated an inverse correlation between IL-1β and TGFβ expression in the TMJ. IL-1β etiologically correlated with joint pathology, whereas TGFβ expression associated with IL-1β down-regulation and improvement of articular pathology. Better understanding of the underlying inflammatory processes during disease will potentially enable us to harness inflammation for orofacial tissue regeneration.

Keywords: IL-1β, TMJ pathology, TGFβ

Introduction

Osteoarthritis (OA) is a progressively destructive joint disorder with articular cartilage erosions and fibrillations, as well as clustering and proliferation of articular chondrocytes (Hamerman, 1989; Andriamanalijaona et al., 2003; Clements et al., 2003). The prevalence of OA in the population over the age of 40 is as high as 90% (Frey et al., 1999). Age-related changes are characterized by significant reduction of cellularity, glycosaminoglycan content, and synthesis of collagen (Livne, 1994; Temple et al., 2007). Recent studies have implicated inflammatory processes in OA pathogenesis (Rosen et al., 1997; Fukui et al., 2003; Lai et al., 2006). IL-1β levels were found to increase during early stages of OA (Pelletier and Martel-Pelletier, 1989), leading to cartilage breakdown and the inhibition of proteoglycan synthesis (Goldring et al., 1996; Martel-Pelletier et al., 1999; Westacott and Sharif, 1999; Scharstuhl et al., 2002; Blaney-Davidson et al., 2005; Lai et al., 2006). OA pathology is also characterized by a hypertrophic response at early disease stages, including articular chondrocyte proliferation and the expression of growth factors as part of an attempted repair process (Andriamanalijaonaet al., 2003; Wadhwa et al., 2005). To this end, TGFβ promotes the formation of extracellular matrix and stimulates chondrocyte proliferation (Villigeret al., 1993; Blaney-Davidson et al., 2005).

The purpose of the present study was to investigate the relationship of IL-1β and TGFβ in TMJ osteoarthritis. The TMJ differs anatomically from other joints (i.e., knee) in both composition, since it is comprised of fibrocartilage, and function, since it is exposed to limited load-bearing forces, such as mastication (Tanaka et al., 2008). Nevertheless, the TMJ, like the knee and other joints, develops OA with aging (Livne, 1994). However, OA in load-bearing joints appears to develop more rapidly than in the TMJ. By 6 months of age in mice, complete erosion of the articular cartilage was found in the knee, while only early histological osteoarthritic lesions were detected in the TMJ (Wadhwa et al., 2005). These differences between the knee and the TMJ can be partly explained by differences in force magnitude applied to joints, causing a greater amount of articular degeneration (Temple et al., 2007).

We hypothesized that a balance between IL-1β and TGFβ underlies the development of TMJ osteoarthritis, whereby IL-1β signaling down-regulates TGFβ expression as part of disease pathology. To address this hypothesis, we used two mouse models of TMJ osteoarthritis, the first occurring naturally with age in the TMJ of wild-type mice, and the second model in the Col1-IL1βXAT transgenic mouse (Lai et al., 2006). The Col1-IL1βXAT transgenic mouse served as the substrate for somatic mosaic analysis, a method for altering the composition of somatic cells in specific areas of the body, hence creating a mosaic of somatic cells. In this transgenic mouse, the pro-collagen I promoter (Col1) drives the expression of the transcriptionally dormant gene Col1-loxP-STOP-loxP-IL1β-IRES-lacZ-pA (Col1-IL1βXAT). The Col1-IL1βXAT is an eXcisionally Activated Transgene (XAT) based on the Cre/loxP molecular genetic method that utilizes a germline-transmitted recombinational substrate containing a dormant transcription unit coupled to somatic gene transfer of Cre recombinase to activate the gene of interest (Lai et al., 2006; Kyrkanides et al., 2007; Fiorentino et al., 2008). Delivery of Cre recombinase was accomplished via the injection of the defective, recombinant feline immunodeficiency viral vector, FIV(Cre), into the TMJs of 2-month-old mice (Lai et al., 2006; Kyrkanides et al., 2007; Fiorentino et al., 2008). Therefore, we evaluated changes in IL-1β and TGFβ expression in the TMJs of WT and Col1-IL1βXAT mice as they relate to the development of OA with aging.

Materials & Methods

Animal Studies

All animal procedures were approved by the Institutional Animal Care and Use Committee prior to the initiation of the study.Wild-type mice, IL1RI-/- knockout mice (Jax Laboratories, Manassas, VA, USA) and Col1-IL1βXAT transgenic mice (Laiet al., 2006) were used on a pure C57/Bl6 strain background. We accomplished deletion of the IL-1β type I receptor (IL1RI) in the Col1-IL1βXAT transgenic mice by crossing the IL1RI-/- knockout mice into Col1-IL1βXAT transgenic mice. Two-month-old Col1-IL1βXAT transgenic mice were injected with 10 µL of FIV(Cre) in the right and left TMJs (a total of 1 x 106 infectious particles) by means of a 271/2 gauge needle under surgical anesthesia (ketamine 40 mg/Kg IP). Additional groups of Col1-IL1βXAT mice received TMJ injections of the control vector FIV(gfp), encoding for the reporter gene green fluorescent protein at the same titer as FIV(Cre), controlling for the viral injection. Additional mice received an equal volume of saline controlling for the injection procedure. The mice were killed at 2 and 6 mos after injections, and their skulls were harvested and immersed in 10% formalin solution for fixation. In total, 26 Col1-IL1βXAT transgenic mice (13 males and 13 females) were used in this study. Nine Col1-IL1βXAT transgenic mice received FIV(Cre) injection (5 mice were killed at 2 mos and 4 mice at 6 mos after viral transduction), and 9 received FIV(gfp) in their TMJs (5 mice were killed at 2 mos and 4 mice at 6 mos after viral transduction). In addition, 8 (5 males, 3 females) Col1-IL1βXAT;IL1RI-/- compound mice were injected with FIV(Cre) in the TMJ (4 mice were killed at 2 mos and 4 mice at 6 mos after viral transduction). In addition, 13 wild-type mice (7 males, 6 females) were used in this study, with 5 mice killed at 2 mos, 4 mice at 6 mos, and 4 mice at 12 mos of age. An additional 13 IL1RI-/- knockout mice (5 males, 8 females) were also included in the study: 5 mice were killed at 2 mos, 4 mice at 6 mos, and 4 mice at 12 mos of age.

Histology

Following fixation in 10% formalin, the mouse heads were dissected, de-fleshed, and decalcified by immersion in an EDTA solution for 7 days at 4°C under constant agitation. The TMJs were processed in a RHS-1 microwave tissue processor (Hacker Instruments, Winnsboro, SC, USA), and then embedded in paraffin, cut into 5-µm-thick sections, and collected on glass slides. Each animal contributed 2 joints (left and right TMJs), and each joint was represented once in our analysis. The sections represented mid-sagittal portions of the TMJ. Histopathology was evaluated by Alcian blue-orange G histochemistry on a scale of 0-4 as previously described (Wilhelmi and Faust, 1976; Lai et al., 2006; Kyrkanides et al., 2007; Fiorentino et al., 2008). Briefly, this scale is defined as: 0 = no apparent changes; 1 = superficial erosions, articular fibrillations, or striations; 2 = injuries limited to uncalcified cartilage; 3 = defects extending into calcified cartilage; and 4 = defects extending into calcified bone. We assessed articular chondrocyte cloning by counting the number of lacunae containing 2 or more articular chondrocytes under 40X magnification and subsequently averaged them per TMJ section.

Immunohistochemical (IHC) analysis was performed for several antigens with the antibodies described below. Sections were rehydrated in PBS for 60 min and bleached in 3% H2O2 for 15 min. Tissues were blocked with appropriate normal serum (4% solution in PBS) followed by overnight incubation in primary antibody solution at room temperature. The tissue was then rinsed in PBS, blocked by appropriate serum (4% solution in PBS), and incubated in the appropriate biotinylated secondary antibody solution for 90 min, followed by PBS rinse and incubation in ABC solution (Vector Laboratories, Burlingame, CA, USA) for 90 min. Immunoreactivity was developed with Nickel–DAB. The histological sections were evaluated by light microscopy with an Olympus BX51 microscope. Microphotographs were captured by means of a Spot CCD digital camera attached to the microscope. The antibodies were a rabbit anti-murine IL-1β polyclonal antibody (Antigenix America, Huntington Station, NY, USA) at 0.2 µg/mL; rabbit anti–human (mature) IL-1β polyclonal antibody (Abcam, Cambridge, MA, USA) used at 1 µg/mL; and rabbit anti–TGFβ polyclonal antibody (Santa Cruz Biotechnology, Santa Cruz, CA, USA) at 1 µg/mL. Control conditions included tissue sections that were processed by immunohistochemistry in the absence of a primary antibody. The number of cells staining positive after immunohistochemistry were counted in each TMJ section under 40X by one investigator (SK). All tissue sections were processed simultaneously for every antigen.

Statistical Analysis

Data were compared by analysis of variance and Tukey’s post hoc tests. P values less than 0.05 were considered significant.

Results

Wild-type Mice Spontaneously Develop TMJ Arthritis with Age

Wild-type mice were evaluated at 2, 6, and 12 mos of age for changes in TMJ histology by Alcian blue-orange G histochemistry. Overall, 2-month-old wild-type mice displayed normal TMJ histology (Fig. 1A). However, by 6 mos of age, the mice displayed joint pathology in the TMJ (Fig. 1B), which was spontaneously attenuated by 12 mos of age (Fig. 1C). We assessed the expression of IL-1β in the TMJ and found a significant increase in the number of IL1β-positive cells in the 6-month-old animals (Figs. 1F, 2C), occurring concurrently with the highest degree of TMJ pathology (Figs. 2A, 2B, 2C). Conversely, IL-1β expression decreased to near-normal levels in 12-month-old mice (Figs. 1G, 2C), when articular pathology spontaneously ameliorated (Figs. 1C, 2C). Abrogation of IL-1β signaling in IL1RI-/- mice prevented joint pathology (Fig. 1D).

Figure 1.

Figure 1.

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Wild-type mice spontaneously develop arthritis-like TMJ pathology. (A) Two-month-old C57Bl6 wild-type mice showed normal TMJ histology (score = 1). However, (B) when they were 6 mos of age, we observed histopathological changes, including loss of normal cyto-architecture, decreased articular cellularity, and chondrocyte cloning (score = 2). (C) The aforementioned joint pathology was partially ameliorated by 12 mos of age (score = 1). (D) Abrogation of IL-1 signaling following targeted deletion of the type I receptor for IL-1 (IL1RI-/- knockout mice) normalized joint histology (score = 1). (E) IL-1β expression was evaluated by immunohistochemistry and was found to be low in 2-month-old mice, but (F) was found to be increased at 6 mos of age. Furthermore, (G) IL-1β immunoreactivity was found to be reduced at 12 mos of age. (H) Deletion of the IL1RI receptor did not affect IL-1β expression in 6-month-old mice. Moreover, (I) we observed elevated TGFβ expression at 2 mos of age, which (J) was reduced in 6-month-old mice. Moreover, (K) TGFβ immunoreactivity was restored at 12 mos of age. (L) Deletion of the IL1RI receptor restored the aforementioned TGFβ down-regulation in 6-month-old mice. Bar = 100 µm.

Figure 2.

Figure 2.

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IL-1β expression is associated with articular pathology and TGFβ down-regulation in the TMJ. (A) TMJ pathology was evaluated by a 1-to-4 scale introduced by Wilhelmi and Faust (1976) in the TMJs of wild-type C57/Bl mice over time. (B) We used articular cloning as an additional method of assessing arthritis-like changes in the TMJ. (C) The levels of IL-1β and TGFβ expression, presented as numbers of immunoreactive cells staining positive for these two antigens, are presented. Please note the inverse relationship of IL-1β and TGFβ expression levels in the TMJ, which changes with time. Furthermore, note how increased IL-1β temporally correlates with higher articular pathology levels in 6-month-old wild-type mice, whereas higher TGFβ levels temporally correlate with low articular pathology levels. In total, 26 Col1-IL1βXAT transgenic mice (13 males and 13 females) were used in this study. Nine Col1-IL1βXAT transgenic mice received FIV(Cre) injection (5 mice were killed at 2 mos and 4 mice at 6 mos after viral transduction), and 9 received FIV(gfp) in their TMJ (5 mice were killed at 2 mos and 4 mice at 6 mos after viral transduction). In addition, 8 (5 males, 3 females) Col1-IL1βXAT;IL1RI-/- compound mice were injected with FIV(Cre) in the TMJ (4 mice were killed at 2 mos and 4 mice at 6 mos after viral transduction). In addition, 13 wild-type mice (7 males, 6 females) were used in this study, with 5 mice killed at 2 mos, 4 mice at 6 mos, and 4 mice at 12 mos of age. An additional 13 IL1RI-/- knockout mice (5 males, 8 females) were also included in the study: 5 mice were killed at 2 mos, 4 mice at 6 mos, and 4 mice at 12 mos of age. Mean (± SEM). *p < 0.05.

We then assessed TGFβ expression in the TMJ, since this growth factor was previously associated with joint regeneration. We found that TGFβ levels changed inversely with IL-1β (Fig. 2C). We observed high levels of TGFβ expression in 2- (Fig. 1I) and 12-month-old mice (Fig. 1K), concurrently with low IL-1β expression (Figs. 1E and 1G, respectively). Conversely, low levels of TGFβ expression were observed in 6-month-old mice (Fig. 1J), concurrently with high levels of IL-1β expression (Fig. 1F) and an increased degree of joint histopathology (Fig. 1B).

IL-1β Signaling Modulates TGFβ Expression in the TMJ

TGFβ appears to have a steady-state expression in healthy TMJ tissues (Figs. 1I, 1K), corresponding to low IL-1β levels of expression (Figs. 1E, 1G). However, increased IL-1β expression, as observed in 6-month-old mice (Figs. 1F, 2C), corresponded to TGFβ down-regulation (Figs. 1J, 2C). Furthermore, deletion of the IL1RI receptor abrogated the negative regulatory effects of IL-1β on TGFβ expression (Figs. 1H, 1L). Taken together, the aforementioned observations suggest IL-1β inhibiting TGFβ expression through the IL1RI receptor.

To investigate further the relationship of IL-1β and TGFβ in vivo, we over-expressed IL-1β in the TMJs of adult Col1-IL1βXAT mice and evaluated TGFβ expression and TMJ histopathology. Two months following the induction of IL-1β, we observed TMJ osteoarthritis (Fig. 3A) concurrently with TGFβ down-regulation (Fig. 3I). Six months following IL-1β induction in Col1-IL1βXAT mice, we observed amelioration of the joint pathology (Fig. 3B). This occurred spontaneously after IL-1β down-regulation (Fig. 3F), apparently due to transgene silencing, which also allowed for homeostatic up-regulation of TGFβ (Fig. 3J). Hence, IL-1β signaling negatively regulated TGFβ signaling during the development of arthritis (Fig. 4). This was also seen following IL1RI receptor deletion, since TGFβ expression and TMJ histology were restored in Col1-IL1βXAT ;IL1RI-/- mice.

Figure 3.

Figure 3.

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IL-1β over-expression in the TMJ induces arthritis-like pathology and decreases TGFβ expression. Injection of FIV(Cre) into the TMJs of Col1-IL1βXAT transgenic mice resulted (A) in the development of arthritis-like pathology, including normal cyto-architecture, decreased articular cellularity, and chondrocyte cloning (score = 3). With time, however, (B) the observed joint pathology ameliorated spontaneously (score = 1). In addition, (C) ablation of IL-1β signaling resulted in the prevention of joint pathology development, as observed in Col1-IL1βXAT;IL1RI-/- compound mice (score = 1). (D) Injection of the control vector FIV(gfp), encoding for the reporter gene green fluorescent protein, did not induce any articular changes in the Col1-IL1βXAT transgenic mice (score = 1). IL-1β immunoreactivity correlated with the development of articular pathology, (E) was increased at the 2-month time-point, and (F) decreased at 6 mos due to transgene silencing. (G) Deletion of the IL1RI receptor did not alter IL-1β expression by articular chondrocytes. (H) Injection of the control vector FIV(gfp) did not IL-1β over-expression in the TMJ. Moreover, we evaluated TGFβ immunoreactivity in the TMJ during the aforementioned conditions and found (I) that TGFβ expression was decreased following the injection of FIV(Cre) into the TMJ of Col1-IL1βXAT transgenic mice. Conversely, (J) TGFβ expression was normalized in TMJs experiencing transgene silencing 6 mos after FIV(Cre) injection into the TMJ of Col1-IL1βXAT transgenic mice. (K) TGFβ expression was also restored in Col1-IL1βXAT;IL1RI-/- compound mice. (L) Col1-IL1βXAT transgenic mice injected with the control vector FIV(gfp) showed normal levels of TGFβ immunoreactivity in the TMJ.

Figure 4.

Figure 4.

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Spontaneous amelioration of joint pathology following IL-1β over-expression in the TMJ of Col1-IL1βXAT transgenic mice. Transgene activation and IL-1β induction in the TMJ of the Col1-IL1βXAT mouse model resulted in the development of joint pathology 2 mos after viral transduction. At 6 mos after viral transduction, however, we observed a spontaneous amelioration of the joint pathology, concomitantly with a reduction in human hIL-1β expression in the TMJ, due to apparent transgene silencing. At the same time, the level of TGFβ expression was significantly increased at the 6-month time-point compared with the 2-month time-point (P < 0.001). Deletion of the IL1RI receptor in this mouse model prevented the development of joint pathology, despite the induction of transgenic IL-1β. Abrogation of IL-1 signaling allowed for increased TGFβ levels of expression. In total, 26 Col1-IL1βXAT transgenic mice (13 males and 13 females) were used in this study. Nine Col1-IL1βXAT transgenic mice received FIV(Cre) injection (5 mice were killed at 2 mos and 4 mice at 6 mos after viral transduction), and 9 received FIV(gfp) in their TMJs (5 mice were killed at 2 mos and 4 mice at 6 mos after viral transduction). In addition, 8 (5 males, 3 females) Col1-IL1βXAT;IL1RI-/- compound mice were injected with FIV(Cre) in the TMJ (4 mice were killed at 2 mos and 4 mice at 6 mos after viral transduction). In addition, 13 wild-type mice (7 males, 6 females) were used in this study, with 5 mice killed at 2 mos, 4 mice at 6 mos, and 4 mice at 12 mos of age. An additional 13 IL1RI-/- knockout mice (5 males, 8 females) were also included in the study: 5 mice were killed at 2 mos, 4 mice at 6 mos, and 4 mice at 12 mos of age. Mean (± SEM).

Discussion

Analysis of the aforementioned data demonstrates spontaneous development of TMJ osteoarthritis in wild-type mice with age, in accordance with reports from previous studies (Wadhwa et al., 2005). Similarly, human joints also develop osteoarthritis as a result of aging (DeBont et al., 1985a,b; Ribeiro et al., 1997; Nebbe and Major, 2000). The role of pro-inflammatory cytokines (IL-1β, TNFα, IL-6) in the development of OA in mammals has been previously suggested (Krauss and Shu, 1997; Goldring and Goldring, 2004). Smith et al. (1997) examined the levels of IL-1α and IL-1β in synovial membranes from persons with OA and suggested that chronic inflammatory changes induced by IL-1β are characteristic of early OA. Moos et al. (1999) demonstrated that IL-1β was up-regulated in cartilage harvested from knee or hip joints derived from persons with OA compared with healthy individuals. Webb et al. (1998) demonstrated that OA synovium supernatants contained higher concentrations of interleukin-1β than normal synovial supernatants. Furthermore, IL-1β levels were found to be increased in synovial tissue harvested from persons suffering from TMJ disorders when compared with healthy individuals (Ogura et al., 2002; Suzuki et al., 2002).

Early stages of OA are characterized by activation and proliferation of chondrocytes, which start forming clusters and actively produce matrix molecules, including collagen II (Mankin, 1974; Silbermann and Livne, 1979; Brandt, 1991; Guerne et al., 1995; Rosen et al, 1997; Barbero et al., 2004). This hypertrophic reaction has been considered to be an attempt at articular repair. TGFβ has been previously proposed as one of the best candidate genes to stimulate cartilage repair (Rédini, 1993; Pujol et al., 1994, 1999; Hunziker, 2001). There are several ways by which TGFβ can be involved in articular regeneration. First, TGFβ has profound effects on the differentiation and proliferation of chondrocytes (Villiger et al., 1993; Hering et al., 2001; Bira et al., 2005). Second, proteoglycan synthesis is enhanced and proteases are down-regulated (Serra et al., 1997; Scharstuhl et al., 2002). A significant down-regulation of TGFβ was observed in aged mice compared with young ones (Serraet al., 1997; Scharstuhl et al., 2002; Xiang et al., 2006). In our studies, IL-1β up-regulation in the TMJ corresponded with TGFβ down-regulation and increased levels of joint pathology. In addition, accelerated over-expression of IL-1β in the adult mouse TMJ resulted in the inhibition of TGFβ expression, which was prevented after abrogation of IL1RI signaling.

In conclusion, our studies in wild-type mice, as well as the Col1-IL1βXAT mouse model of osteoarthritis, demonstrated an inverse correlation between IL-1β and TGFβ expression in the TMJ. IL-1β correlated etiologically with joint pathology, whereas TGFβ expression was associated with IL-1β down-regulation and improvement of articular pathology. Better understanding of the underlying inflammatory processes during disease will potentially enable us to harness inflammation for orofacial tissue regeneration.

Footnotes

This work was funded by grants DE017765 and AR055035 from the National Institutes of Health.

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