Pathophysiology and pharmacologic control of osseous mandibular condylar resorption.

PURPOSE: When osseous mandibular condylar resorption occurs there can be many different diagnoses: inflammatory arthritis, TMJ compression, trauma, hormone imbalances, and others. While each diagnosis has its own original inciting event, the pathophysiological pathway for articular bone loss is the same. The aim of this article is to review the relevant literature on condylar resorption and the use of pharmacotherapy to control arthritic erosions and resorption. MATERIALS AND METHODS: The literature search was performed using PubMed database with various combinations of related keywords. Preference was given to clinical trials when reviewing articles. RESULTS: The literature reveals that common cellular level events associated with articular resorption include the activation of osteoblasts by cytokines, free radicals, hormone imbalances and/or potent phospholipid catabolites. The osteoblast then activates the recruitment of osteoclasts and promotes the release of matrix degrading enzymes from the osteoclast. Research into articular erosions has focused on elucidating the important steps in the bone destructive pathways and interfering with them by pharmacological means. The use of antioxidants, tetracyclines, omega-3 fatty acids, non-steroidal anti-inflammatories and inflammatory cytokine inhibitors to aid in preventing and controlling articular bone loss including osseous mandibular condylar resorption has been successful. CONCLUSION: By understanding the known pathways that lead to condylar resorption and the individual patient's susceptibilities, targeted pharmacotherapy might be able to disturb these pathways and prevent further condylar resorption. Basic clinical investigations and randomized clinical trials are still required, but the present science is encouraging.

Regulation of κ-opioid receptor signaling in peripheral sensory neurons in vitro and in vivo.

There is considerable interest in understanding the regulation of peripheral opioid receptors to avoid central nervous system side effects associated with systemically administered opioid analgesics. Here, we investigated the regulation of the κ-opioid receptor (KOR) on rat primary sensory neurons in vitro and in a rat model of thermal allodynia. Under basal conditions, application of the KOR agonist trans-(1S,2S)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide hydrochloride hydrate (U50488) did not inhibit adenylyl cyclase (AC) activity nor release of calcitonin gene-related peptide (CGRP) in vitro and did not inhibit thermal allodynia in vivo. However, after 15-min pretreatment with bradykinin (BK), U50488 became capable of inhibiting AC activity, CGRP release, and thermal allodynia. Inhibition of AC by 5-hydroxytryptamine 1 or neuropeptide Y(1) receptor agonists and stimulation of extracellular signal-regulated kinase activity by U50488 did not require BK pretreatment. The effect of U50488 in BK-primed tissue was blocked by the KOR antagonist nor-binaltorphimine both in vitro and in vivo. The effect of BK in vitro was blocked by either indomethacin or bisindolylmaleimide, suggesting that an arachidonic acid (AA) metabolite and protein kinase C (PKC) activation mediate BK-induced regulation of the KOR system. Furthermore, the effect of U50488 in BK-treated tissue was blocked by a soluble integrin-blocking peptide (GRGDSP), but not the inactive reverse sequence peptide (GDGRSP), suggesting that, in addition to AA and PKC, RGD-binding integrins participate in the regulation of KOR signaling in response to U50488. Understanding the mechanisms by which peripheral KOR agonist efficacy is regulated may lead to improved pharmacotherapy for the treatment of pain with reduced adverse effects.

17beta-estradiol rapidly enhances bradykinin signaling in primary sensory neurons in vitro and in vivo.

Many studies have demonstrated that premenopausal women are at increased risk for various pain disorders. Pain-sensing neurons, termed "nociceptors," in the trigeminal ganglia (TG) and dorsal root ganglia (DRG) express receptors for inflammatory mediators and noxious physical stimuli and transmit signals for central processing of pain sensation. Estrogen receptors (ERs) are also expressed on nociceptors in the TG and DRG, and there is ample literature to suggest that activation of ERs can influence pain mechanisms. However, the mechanism for ER modulation of nociceptor activity is incompletely understood. The aim of this study was to characterize the effect of 17ß-estradiol (17ß-E(2)) on signaling of the inflammatory mediator bradykinin (BK) in primary cultures of rat sensory neurons and a behavioral model of thermal allodynia in rats. Here, we show that exposure to 17ß-E(2) rapidly (within 15 min) enhanced responses to BK in vitro and in vivo. The 17ß-E(2)-mediated enhancement of BK signaling was not blocked by the transcription inhibitor anisomycin and was mediated by a membrane-associated ER. The effect of 17ß-E(2) to enhance BK responses required activation of ß1-containing, RGD-binding integrins. These data show that 17ß-E(2) rapidly enhances inflammatory mediator responses both in vitro and in vivo and suggest that 17ß-E(2) acting at primary sensory pain neurons may participate in regulating the sensitivity of women to painful stimuli.

Fibronectin stimulates TRPV1 translocation in primary sensory neurons.

Extracellular matrix (ECM) molecules are highly variable in their composition and receptor recognition. Their ubiquitous expression profile has been linked to roles in cell growth, differentiation, and survival. Recent work has identified certain ECM molecules that serve as dynamic signal modulators, versus the more-recognized role of chronic modulation of signal transduction. In this study, we investigated the role that fibronectin (FN) plays in the dynamic modulation of transient receptor potential family V type 1 receptor (TRPV1) translocation to the plasma membrane in trigeminal ganglia (TG) sensory neurons. Confocal immunofluorescence analyses identify co-expression of the TRPV1 receptor with integrin subunits that bind FN. TG neurons cultured upon or treated with FN experienced a leftward shift in the EC(50) of capsaicin-stimulated neuropeptide release. This FN-induced increase in TRPV1 sensitivity to activation is coupled by an increase in plasma membrane expression of TRPV1, as well as an increase in tyrosine phosphorylation of TRPV1 in TG neurons. Furthermore, TG neurons cultured on FN demonstrated an increase in capsaicin-mediated Ca(2+) accumulation relative to neurons cultured on poly-D-lysine. Data presented from these studies indicate that FN stimulates tyrosine-phosphorylation-dependent translocation of the TRPV1 receptor to the plasma membrane, identifying FN as a critical component of the ECM capable of sensory neuron sensitization.

Local blockade of integrins in the temporomandibular joint region reduces Fos-positive neurons in trigeminal subnucleus caudalis of female rats produced by jaw movement.

This study assessed the influence of integrins on trigeminal brainstem neural activity evoked during jaw movement (JM). Limited range of motion and pain during jaw opening are common complaints of patients with temporomandibular joint (TMJ) disorders. JM (0.5 Hz, 30 min) was presented to ovariectomized (OvX) female rats given estrogen replacement and males under barbiturate anesthesia. Quantification of Fos-like immunoreactivity (Fos-LI) after JM served as an index of evoked neural activity. Rats were injected locally in the TMJ with either an active (GRGDS, 300 microM, 25 microl) or an inactive integrin antagonist (SDGRG) prior to JM. The effect of prior inflammation of the TMJ region was assessed in separate groups of rats by injecting bradykinin (10 microM, 25 microl) with or without integrin drugs prior to JM. Active integrin antagonist significantly reduced JM-evoked Fos-LI in superficial laminae at the trigeminal subnucleus caudalis/upper cervical cord (Vc/C2) junction in OvX compared to male rats independent of bradykinin pretreatment. Fos-LI produced in the dorsal paratrigeminal and trigeminal subnucleus interpolaris/caudalis (Vi/Vc) transition regions was not reduced by active integrin antagonist in males or OvX females. Active integrin antagonist did not affect Fos-LI produced after injection of bradykinin alone into the TMJ. These results suggest that RGD binding integrins contribute to JM-evoked neural activity at the Vc/C2 junction under naive and inflamed conditions in a sex-dependent manner.

Free radical damage in facsimile synovium: correlation with adhesion formation in osteoarthritic TMJs.

PURPOSE: The purpose of this study was to use the rat air pouch model of facsimile synovium to evaluate oxidative stress as a primary mechanism in the pathogenesis of degenerative temporomandibular joint (TMJ) disease. MATERIALS AND METHODS: Forty-nine Sprague-Dawley adult female rats were used to generate the standard rat air pouch model of facsimile synovium. This was accomplished by daily air injections (20 cc) subdermally through the dorsal skin. Hydrogen peroxide and ferrous iron (components of the Fenton reaction which generate free radicals) were introduced into the pouches of the 4-, 7-, and 14-day groups to generate oxidative stress. Control rats were injected with phosphate-buffered solution (PBS), pH 7.4. Either N-acetylcysteine (NAC), a powerful free radical scavenger, or ibuprofen were simultaneously injected with the Fenton reagents into the pouches of the 14-day treatment groups to modulate free radical-mediated protein damage to the synovium. Animals were euthanized at appropriate experimental intervals and biopsies obtained from specimens to analyze: (1) proteins' amino acid modification (carbonyl group formation), (2) protein hydrophobicity, (3) detection of low molecular weight protein degradation products, and (4) histological and gross anatomical observations. RESULTS: Free radicals introduced into the rat air pouch interacted with synovial tissues causing oxidation and breakdown of proteins. Clinical evidence of adhesion formation consistent with features found in osteoarthritis of the TMJ developed. The groups subjected to oxidative stress experienced statistically significant (p < 0.05) increases in carbonyl formation, carbonyls/protein, and low molecular weight protein fragments. These groups also showed significant (p < 0.05) hydrophobicity changes consistent with free radical attack. Control synovial tissues were statistically undamaged. The 14-day NAC and ibuprofen treatment groups experienced statistically significant (p < 0.05) decreases in total carbonyl formation, carbonyls/protein, and hydrophobicity. Histological and gross observations in free radical damaged synovium exhibited features consistent with known arthoscopic and arthrocentesis findings in diseased TMJs. CONCLUSIONS: This study suggests that the rat air pouch model of facsimile synovium develops clinical evidence of adhesions and biochemical signs of protein modification when subjected to free radical attack. NAC and ibuprofen prevented carbonyl formation as well as hydrophobicity changes indicative of oxidative stress damage in facsimile synovium. These findings are consistent with features of degenerative human TMJ disease. Future direction may be taken from this study to postulate new analysis techniques and treatment modalities for patients with degenerative TMJ disease.

Pathogenesis of degenerative temporomandibular joint arthritides.

Over the past decade, remarkable progress has been made in the study of molecular mechanisms involved in degenerative temporomandibular joint arthritides. Based on recent findings, models of degenerative temporomandibular joint disease predict that mechanical loads trigger a cascade of molecular events leading to disease in susceptible individuals. These events involve the production or release of free radicals, cytokines, fatty acid catabolites, neuropeptides, and matrix-degrading enzymes. Under normal circumstances, these molecules may be involved in the remodeling of articular tissues in response to changing functional demands. However, if functional demands exceed the adaptive capacity of the temporomandibular joint or if the affected individual is susceptible to maladaptive responses, then a disease state will ensue. An individual's susceptibility to degenerative temporomandibular joint disease may be determined by several factors, including genetic backdrop, sex, age, and nutritional status. It is hoped that, by furthering our understanding of the molecular events that underlie degenerative temporomandibular joint diseases, improved diagnostics and effective therapies for these debilitating conditions will be developed.

Crosslinking of fibrinogen and fibronectin by free radicals: a possible initial step in adhesion formation in osteoarthritis of the temporomandibular joint.

PURPOSE: Adhesion formation in osteoarthritis (OA) of the temporomandibular joint (TMJ) typically results in a sustained limitation of joint movement. We propose the hypothesis that free-radical-mediated crosslinking of proteins underlies this adhesion formation in affected joints. Free radicals may cause oxidative modification of proteins, creating an opportunity for the formation of intramolecular and intermolecular crosslinks via covalent bonds. This may stabilize protein aggregates, rendering them more resistant to degradation. In this study, the free-radical-mediated crosslinking of model proteins (fibrinogen and fibronectin) was investigated to test our hypothesis that free radicals contribute to adhesion formation via this mechanism in OA of the TMJ. MATERIALS AND METHODS: Physiological clot formation of fibrinogen by thrombin and free-radical-induced crosslinking of fibrinogen and of fibronectin were analyzed using spectrophotometric turbidity measurements, light-scattering techniques, polyacrylamide gel electrophoresis (PAGE), and rotary shadowing. RESULTS: Fibrinogen was shown to aggregate after free radical treatment, as detected using turbidity measurements and light-scattering techniques. Using PAGE, fibrinogen as well as fibronectin was shown to degrade under low oxidative stress. Under high oxidative stress, however, fragments from both proteins were found to be covalently crosslinked, resulting in high-molecular-weight protein aggregates. The aggregation was shown to be at random with rotary shadowing. CONCLUSION: The study shows that high oxidative stress contributes to the formation of crosslinked proteins that may serve as an initial scaffolding for the development of adhesions frequently seen in OA of the TMJ.