The Journal of Steroid Biochemistry and Molecular Biology
Estrogenic effect on swelling and monocytic receptor expression in an arthritic temporomandibular joint model
Introduction
Physical conditions causing temporomandibular joint (TMJ) disorders (TMD) can include muscle pain, disc displacements and joint conditions that include arthralgia, osteoarthritis and ostearthrosis. Large epidemiological studies [1], [2] indicate that women seek treatment for TMD more often than men [3], [4], [5] and women comprise over three-fourths of the clinical TMD cases. Moreover, women appear to exhibit more severe symptoms of TMD [6], [7]. Although the biological basis for this possible gender-based disparity is unclear, the time course of symptoms associated with TMD is of note in females. Peak incidence in TMD occurs during the childbearing years [8] and varies in intensity over the menstrual cycle [9]. Notably, the attenuation of symptoms in post-menopausal women is reversed when they take estrogen supplements [2], [10].
Although the above data strongly suggest that hormonal factors are involved in TMD, the effect of sex hormones on TMD inflammation and the mechanism of these hormonal effects are largely unknown. TMD, especially those associated with acute trauma, internal derangement, or osteoarthritis, often includes an inflammatory component [11], [12], [13]. Estrogen can directly act on monocytes and macrophages to regulate the production of cytokines, e.g., interleukin-1 (IL-1) [14], [15], [16], IL-6 [17] and tumor necrosis factor-α (TNF-α) [18], [19]. Estrogen can modulate monocytes/macrophage function through interaction with the beta form of the estrogen receptor [20]. Cytokines IL-1β and IL-6 have been shown to be inflammatory mediators in the TMJ synovium [21]. IL-1β and TNF-α promote cartilage reabsorption, inhibit synthesis of proteoglycans and cause inflammation, all major symptoms of TMD [22], [23], [24], [25]. Monocytes/macrophages are the major immune cell present within the synovial tissues and are also recruited in high numbers during synovial inflammation, suggesting that a majority of IL-1 and TNF-α release within the joint is from this cell type [26].
A receptor that regulates cytokine production in monocytes/macrophages due to auto-antigen stimulation is the Fc gamma receptor IIIA (CD16) [27]. The functional CD16 receptor consists of an α subunit that spans across the membrane and functions in binding auto-antigens (e.g., rheumatoid factors) and a γ subunit (FcɛRIγ) necessary for receptor assembly and signal transduction [28]. CD16 binding is preferential for small immunoglobulin G (IgG) dimer or trimer complexes that include anti-IgG antibody complexes. This is an important component of auto-antigens and arthritic factors that are potential triggers for onset or maintenance of arthritic diseases [29], [30], [31], [32]. Importantly, significantly high levels of auto-antigens have been detected in the synovial fluid of TMD patients in comparison to healthy individuals [33] and previous studies have shown that CD16 expression and cytokine release are modulated in monocytes/macrophages by estrogen treatment [34].
Knowing estrogen's impact on TMD we tested the effect of estrogen on TMJ swelling and monocytic cell numbers. Moreover, we characterized the level of CD16 receptor expression within the arthritic TMJ animal model to characterize this receptor's role in relaying estrogenic signals.
Section snippets
Animals protocols
The Baylor College of Dentistry's Institutional Animal Care and Use Committee approved the experimental protocol. Intact and ovariectomized (OVX) (200–225 g) Sprague–Dawley rats (Harlan Industries, Houston, TX) were received and housed in individual wire hanging cages in a temperature-controlled (23 °C) room (n = 8 per group). The rats were kept on 12:12 light/dark cycle with lights on at 07:00 h and given food (Teklad 7002, Harlan Industries, Houston, TX) and water ad libitum.
Two days later (see
Results
Plasma E2, likely of adrenal origin, was very low (Fig. 1A) in the non-supplemented OVX group. When compared to the OVX group the artificial estrous cycle group (H-E2-ES) had significantly (p < 0.05) more plasma E2 (Fig. 1A). The group given pregnancy levels of E2 (E2-PRG) had significantly (p < 0.01) higher plasma E2 concentrations (Fig. 1A) than the artificial estrous cycle group.
CFA injection induced significantly higher levels (p < 0.05) of corticosterone when compared to the intact animals with
Discussion
In this study, intact rats, OVX rats and OVX rats supplemented with E2 (i.e., H-E2-ES and E2-PRG groups) were injected with adjuvant CFA in the TMJ space. OVX rats with low levels of E2 were protected from CFA induced TMJ swelling/inflammation. Whereas E2 exacerbated the CFA induced arthritic event, consistent with the clinical observation that TMDs are usually negatively effected by the presence of estrogen [2], [10]. It should be noted that the OVX rats had detectable E2 concentrations that
Acknowledgements
This work was supported by grants DE12657-01, F30DE05726-01, DE016059-01 and DE015372-01 from the NIH institutes National Institute of Dental and Craniofacial Research (NIDCR) and the Office of Research on Women's Health (ORWH).
References (60)
- et al.
Epidemiology of signs and symptoms in temporomandibular disorders: clinical signs in cases and controls
J. Am. Dent. Assoc.
(1990) - et al.
Use of exogenous hormones and risk of temporomandibular disorder pain
Pain
(1997) - et al.
Estimated prevalence and distribution of reported orofacial pain in the United States
J. Am. Dent. Assoc.
(1993) - et al.
Effect of age and sex on craniomandibular disorders
J. Prosthet. Dent.
(1993) - et al.
Relationship between clinical and radiologic findings of the temporomandibular joint in rheumatoid arthritis
Oral Surg. Oral Med. Oral Pathol.
(1988) - et al.
Prostaglandin E2 in temporomandibular joint synovial fluid and its relation to pain and inflammatory disorders
J. Oral Maxillofac. Surg.
(2000) The influence of neuropeptides, serotonin, and interleukin 1beta on temporomandibular joint pain and inflammation
J. Oral Maxillofac. Surg.
(1998)- et al.
Gonadal steroids modulate human monocyte interleukin-1 (IL-1) activity
Fertil. Steril.
(1988) - et al.
17-Beta-estradiol regulates expression of genes that function in macrophage activation and cholesterol homeostasis
J. Steroid Biochem. Mol. Biol.
(2002) - et al.
Synovial fluid cytokines and proteinases as markers of temporomandibular joint disease
J. Oral Maxillofac. Surg.
(1998)
The synovial lining cell: biology and pathobiology
Semin. Arthritis Rheum.
Detection of specific antibodies against human cultured chondrosarcoma (HCS-2/8) and osteosarcoma (Saos-2) cells in the serum of patients with osteoarthritis of the temporomandibular joint
Arch. Oral Biol.
Calcitonin gene-related peptide and substance P immunoreactivity in rat trigeminal ganglia and brainstem following adjuvant-induced inflammation of the temporomandibular joint
Arch. Oral Biol.
Modulation of the inflammatory response in the rat TMJ with increasing doses of complete Freund's adjuvant
Osteoarthritis. Cartilage
Sources of estrogen and their importance
J. Steroid Biochem. Mol. Biol.
Effect of estrogen replacement therapy on natural killer cell activity in postmenopausal women
Maturitas
Meal pattern changes associated with temporomandibular joint inflammation/pain in rats; analgesic effects
Pharmacol. Biochem. Behav.
17-Beta-estradiol and progesterone modulate an intrinsic opioid analgesic system
Brain Res.
Pain thresholds are elevated during pseudopregnancy
Brain Res.
Gender differences in pain
J. Orofac. Pain
Chronic pain and use of ambulatory health care
Psychosom. Med.
Functional impairment in TMJ patient and nonpatient groups according to a disability index and symptom profile
Cranio
Jaw pain prevalence among French-speaking Canadians in Quebec and related symptoms of temporomandibular disorders
J. Dent. Res.
Temporomandibular disorders: MR assessment of inflammatory changes in the posterior disk attachment during the menstrual cycle
J. Comput. Assist. Tomogr.
Is postmenopausal hormone use a risk factor for TMD
J. Dent. Res.
Effect of estradiol on interleukin 1 synthesis by macrophages
Int. J. Immunopharmacol.
Cultured human luteal peripheral monocytes secrete increased levels of interleukin-1
J. Clin. Endocrinol. Metab.
17 beta-Estradiol inhibits expression of human interleukin-6 promoter- reporter constructs by a receptor-dependent mechanism
J. Clin. Invest.
Estrogen inhibits release of tumor necrosis factor from peripheral blood mononuclear cells in postmenopausal women
J. Bone Miner. Res.
Estrogen modulates the expression of tumor necrosis factor alpha mRNA in phorbol ester-stimulated human monocytic THP-1 cells
Lymphokine Cytokine. Res.
Cited by (34)
A Systematic Review of Rat Models With Temporomandibular Osteoarthritis Suitable for the Study of Emerging Prolonged Intra-Articular Drug Delivery Systems
2021, Journal of Oral and Maxillofacial SurgeryCitation Excerpt :The results are shown in Table 1. Seven studies included only female rats,10-16 and 4 included both female and male rats.17-20 In all other studies, only male rats were included.
Estrogen-Mediated MicroRNA-101-3p Expression Represses Hyaluronan Synthase 2 in Synovial Fibroblasts From Idiopathic Condylar Resorption Patients
2019, Journal of Oral and Maxillofacial SurgeryHistological findings in TMJ treated with high condilectomy for internal derangement
2018, Journal of Cranio-Maxillofacial SurgeryENPP1 and ESR1 genotypes influence temporomandibular disorders development and surgical treatment response in dentofacial deformities
2016, Journal of Cranio-Maxillofacial SurgeryCitation Excerpt :IL1 and IL6-β cytokines are found in the synovial membrane of the temporomandibular joint during inflammation (Kubota et al., 1998), whereas TNFα and IL1 produced by monocytes/macrophages will promote cartilage resorption, inhibit proteoglycan synthesis and play a proinflammatory role in most of temporomandibular structures (Pettipher et al., 1986; Saklatvala, 1986). Treatment with estradiol seems then to have a protective effect on TMJ through reducing the number of monocytes in the articular synovial, and through reducing the production of proinflammatory cytokines (Guan et al., 2005; Pacifici, 1996, 1998). In rats, estrogen deficiency during puberty, induced by ovariectomy, predispose to alterations of TMJ by changes in serum levels of calcitonin and parathyroid hormone (Yasuoka et al., 2000).
Infusion of Gabrα6 siRNA into the trigeminal ganglia increased the myogenic orofacial nociceptive response of ovariectomized rats treated with 17β-estradiol
2014, NeuroscienceCitation Excerpt :In these analyses, a meal was defined using a 10-min end of meal criterion (i.e., a meal was bracketed before and after by a 10-min period of no pellets being taken) and the minimum meal size was set at 135 mg [i.e., 3 pellets] (Castonguay et al., 1986). Meal patterns (i.e., food intake, meal size, meal number and meal duration) were calculated using Med Assoc. Inc., and proprietary software (Guan et al., 2005; Kerins et al., 2005; Bellinger et al., 2007; Kramer and Bellinger, 2009; Kramer et al., 2010). Meal duration has been shown to be a continuous, non-invasive measure of orofacial nociception (surface and deep) in undisturbed male and female rats (Kerins et al., 2003, 2005).
Reduced GABA <inf>A</inf> receptor α6 expression in the trigeminal ganglion alters inflammatory TMJ hypersensitivity
2012, NeuroscienceCitation Excerpt :The animals were then sacrificed two days after the TMJ injection and the trigeminal ganglia were harvested for immunocytochemistry and western blots. Meal duration is a proven, dose-dependent behavioral marker of TMJ hypersensitivity in undisturbed male and female rats (Kerins et al., 2005; Guan et al., 2005; Bellinger et al., 2007; Kramer and Bellinger, 2009; Kramer et al., 2010a). In these studies rats were housed individually in 32 sound-attenuated chambers equipped with computer-activated pellet feeders (Med Assoc. Inc., East Fairfield, VT).