Abstract
Lysophosphatidic acid (LPA) receptor (LPA1) signaling plays the key role in initiation of nerve injury-induced neuropathic pain [1-4]. LPA, which is produced in the spinal cord following the sciatic nerve injury causes a calpain-mediated demyelination of dorsal root fibers and sprouting through LPA1 receptor, leading to an induction of synaptic reorganization underlying allodynia. The LPA1 signaling also initiates the up-regulation of Cavα2δ1 in DRG, leading to an enhancement of spinal pain transmission underlying hyperalgesia. Similar LPA1-mediated chronic abnormal pain and underlying mechanisms are observed in mouse models with Meth-A sarcoma surrounding sciatic nerve (cancer model) or with chemotherapy (paclitaxel). Central neuropathic pain following spinal nerve injury is now recently found to include the LPA1-mediated mechanisms. In contrast, (arthritic) inflammatory pain following Complete Freund Adjuvant treatment fails to show the involvement of LPA1 signaling. Thus it seems that many models of neuropathic pain, but not inflammatory pain model include LPA1-mediated mechanisms. Recent studies revealed that another subtype LPA3 receptor plays a crucial role in neuropathic pain mechanisms in terms of LPA biosynthesis. Nerve injury and intrathecal administration of LPA increased the levels of lysophosphatidylcholine (LPC) and LPA in the spinal dorsal horn and dorsal root with peaks at 1 - 2 h. We obtained the evidence for in vitro LPA biosynthesis in spinal dorsal horn and dorsal root as well as in vivo one. In these studies we successfully identified the species of LPC and LPA molecules by use of Mass Spectrometery. Major species are the molecules with lipid chain 16:0, 18:0 or 18:1, and their contents were all time-dependently increased by nerve injury. Interestingly, there was an LPA-induced amplification of LPA biosynthesis through an activation of LPA3 receptor and microglia. The microglial involvement was found to play key roles as an initiation of neuropathic pain mechanisms including LPA3-mediated amplification of LPA biosynthesis.
Highlights
Acute isolated neurological syndromes, such as optic neuropathy or transverse myelopathy, may cause diagnostic problems since they can be the first presentations in a number of demyelinating disorders including multiple sclerosis (MS) and collagen diseases
tumor necrosis factor (TNF) therapy and demyelinating event: A report indicates that adverse events such as the demyelinating lesion in the brain, optic neuritis, and neuropathy occurred after treatment with anti-TNF alpha therapy in collagen disease, and TNF antagonizing therapy showed worsening in a clinical trial with MS
Believing on the similarities of normal joints in humans and monkeys, we have employed a model of collagen-induced arthritis in Macaca fascicularis in an attempt to evaluate the histological alterations caused by such condition in the extracellular matrix of the articular cartilage
Summary
Acute isolated neurological syndromes, such as optic neuropathy or transverse myelopathy, may cause diagnostic problems since they can be the first presentations in a number of demyelinating disorders including multiple sclerosis (MS) and collagen diseases. Acute Serum Amyloid A (A-SAA) is an acute phase protein strongly expressed in rheumatoid arthritis (RA) synovial tissue (ST) critically involved in regulating cell migration and angiogenesis These processes are dependent on downstream interactions between extracellular matrix and cytoskeletal components. Conclusions: These results indicate that Egr-1 contributes to IL-1mediated down-regulation of PPARg expression in OA chondrocytes and suggest that this pathway could be a potential target for pharmacologic intervention in the treatment of OA and possibly other arthritic diseases. Immune cell-derived microparticles (MPs) are present at increased amounts in synovial fluid of rheumatoid arthritis (RA) patients [1] and can activate disease-relevant signalling pathways in RA synovial fibroblasts (SF) [2,3].
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