Neurogenic Contributions to the Initiation and Persistence of Arthritis

Terry A. McNearney

The University of Texas Medical Branch at Galveston

Funded in June, 2002: $300000 for 4 years


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Neurogenic Contributions to the Initiation and Persistence of Arthritis

More than 90% of the U.S. population will suffer some form of arthritis in their lifetime, costing the economy an estimated 60 billion dollars a year on treatment and disability. Currently available therapies do not approach or maintain complete clinical remissions, suggesting that additional pathways can rekindle arthritic responses. A neurogenic contribution to arthritis has long been appreciated, with multiple case reports of arthritis sparing or reversing on the patient's paralyzed side after stroke or nerve injury.

We have both clinical and laboratory data that support the hypothesis that the neurotransmitter glutamate (GLU), likely released by peripheral nerves, contributes to signal transduction events capable of evoking inflammatory cascades. We have demonstrated that intra-articular activation with GLU receptor agonists alters electrophysiologic, neurochemical, clinical, and behavioral changes in the joint associated with active experimental (kaolin/carrageenan) arthritis in rats. Interruption of the nerves supplying the joint or GLU receptor blockade abrogates the inflammatory response and above parameters by at least 50%. Pilot studies using the complete Freund's adjuvant (CFA) intra-articular injection model in rats, which more closely mimics a chronic arthritis course such as rheumatoid arthritis in humans, demonstrate that nociceptive-related behaviors normalize with nerve disruption using capsaicin pretreatment or with kinase inhibitors.

We have also reported increased levels of excitatory amino acids (EAA) in synovial fluid (SF) in human active arthropathies and animal arthritis models. The EAA, including GLU and aspartate (ASP), demonstrate fluctuations over time correlating with the clinical profile. Regression analysis suggests that SF GLU and ASP levels correlate with SF chemokine levels (RANTES, MIP-1α and IL-8) in human synovial fluid (SF) samples, independent of SF TNF-α levels. The above studies in rat and human arthritis suggest a novel pathway by which the inflammatory response can be manipulated independent of principal and traditional cytokine mediators.

To test the hypothesis that neurotransmitter glutamate is a novel neurogenic initiator in arthritic inflammation, the proposed studies include the CFA animal model as well as primary and clonal synoviocyte culture models that can be used to mimic inflammatory arthritis. The culture models can be used (1) to study GLU receptor-mediated signal transduction events under controlled conditions and (2) to more carefully assess efficacy and safety of the inhibitory agents prior to animal testing. Furthermore, the glutamate-activated events can be studied in vitro in the absence of blood-borne mediators, demonstrating the ability of GLU to directly evoke inflammatory cascades.

 Treatment of cultured human synoviocytes (primary cultures or HTB-93 clonal synovial cell line) with GLU agonist NMDA increased the expression of TNF-α, GLU receptor subunit NMDA NR1 and its subcellular distribution toward the nuclear compartment in a dose dependent fashion. These effects can be blocked with tyrosine kinase inhibitor genistein. The dual effect of NMDA on clonal and primary synoviocytes is further enhanced by the metabotropic GLU receptor agonist ACPD, suggesting a role for GLU receptor cooperativity.

Specific Aim 1 will characterize the inflammatory parameters in response to intra-articular CFA injections, measuring dynamic alterations of SF GLU and ASP levels, cytokines, chemokines, and GLU receptor density and subtypes. Pretreatment with capsaicin will also be planned to eliminate neural release of EAA prior to assessment of inflammatory responses.

Specific Aim 2 will determine how glutamate directly impacts signal transduction and intracellular processes resulting in the release of inflammatory cytokines and chemokines, using human HTB-93 and primary synoviocyte cultures and the experimental arthritis model in rats using CFA. These studies will allow design of a treatment system to modulate glutamate receptor activation to modify the arthritic inflammatory response.

Translation of previous findings about glutamate evoked central sensitization mechanisms to events evoking peripheral inflammatory responses has been an ongoing focus in our combined laboratory efforts. Characterization of glutamate receptor activation and signal transduction as a potential therapeutic target in the periphery (joint) may provide clues to interruption of inflammatory and nociceptive (pain) responses. Alone or in tandem with currently available agents, interruption of events initiated by glutamate receptor activation may provide a more effective and long-lasting therapeutic benefit to the inflammation and pain of human arthritis.


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Scientific Results:
Neurotransmitter receptor localization and their associated functions on the target synovial lining cells that we are investigating support our overall hypothesis that glutamate is a neurogenic and maintenance factor in the arthritic joint, as have our previously reported findings.  A primary support of the hypothesis has already been clearly demonstrated with the release of TNF-α and RANTES by glutamate agonists. We have now extended the original hypothesis to other neurogenic neurotransmitter related receptors and channels that we are finding associated with the synoviocyte targets, specifically various types of TRP family receptors and pH sensitive G-protein coupled receptors.

Our preliminary studies with the pH sensing receptor suggest that this receptor has a protective function and a different activation pathway during situations that are characterized by high acidity, such as anoxia or injury. This may provide an important maintenance pathway during periods of pH stress when normal receptor functions can become dormant outside the physiological range. Elucidation of these pH sensitive mechanisms may be very important to circumvent reperfusion injury in synovial lining, muscle and bone, as well as in brain. 

The restoration of paw withdrawal latencies to baseline levels and prevention of knee joint swelling following knee joint injection of capsaicin indicates that intra-articular capsaicin may be a potential clinical therapy affecting both nerve endings and vanilloid receptors on synoviocytes in the articular joints.


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Kochukov M.Y., McNearney T.A., Fu Y., and Westlund K.N.   Thermosensitive TRP ion channels mediate cytosolic calcium response in human synoviocytes.  Am J Physiol Cell Physiol. 2006 Sep;291(3):C424-32.

Christensen B.N., Kochukov M., McNearney T.A., Taglialatela G., and Westlund K.N.  Proton-sensing G protein-coupled receptor mobilizes calcium in human synovial cells.  Am J Physiol Cell Physiol. 2005 Sep;289(3):C601-8.

McNearney T., Baethge B.A., Cao S., Alam R., Lisse J.R., and Westlund K.N.  Excitatory amino acids, TNF-α, and chemokine levels in synovial fluids of patients with active arthropathies.  Clin Exp Immunol. 2004 Sep;137(3):621-7.

Lawand N.B., Reddig W.J., Cashin A.E., Westlund K.N., and Willis W.D.  NMDA receptors and associated signaling pathways: a role in knee joint blood flow regulation.  Eur J Pharmacol. 2004 Sep 19;499(1-2):155-61.

Hendiani J.A., Westlund K.N., Lawand N., Goel N., Lisse J., and McNearney T.  Mechanical sensation and pain thresholds in patients with chronic arthropathies.  J Pain. 2003 May;4(4):203-11.