Skeletal pain associated with bone fracture is another

Skeletal pain associated with bone fracture is another area of critical need for a novel pain medication. NSAIDs and opiates are the two major therapies currently used to manage bone fracture pain. However, both of these therapies lead to significant unwanted side effects. Using the osteotomy model of bone fracture, we have demonstrated an analgesic benefit with compound-1, suggesting the potential utility of autotaxin inhibition as an alternative approach to alleviate pain associated with bone fracture. Since NSAIDs are contra-indicated for bone fracture pain because of their potential interference with the bone healing response, an autotaxin inhibitor could provide a safer alternative approach to treat pain associated with a bone fracture. Additional studies in other models of pain associated with bone fracture would help to further strengthen this observation. An antibody targeting LPA, known as Lpathomab (Lpath, Inc., San Diego, CA), has been shown to be efficacious in several different pain models, including diabetic peripheral neuropathy and chemotherapy-induced neuropathic pain. It would be interesting to test whether inhibition of LPA generation using an autotaxin inhibitor would also afford a therapeutic benefit in these pain states. Mice have recently been generated, wherein autotaxin can be knocked out after birth, and these animals have a normal phenotype without any obvious abnormalities. Subjecting the adult-specific autotaxin knockout mice to models of pain would help further confirm the role of the autotaxin/LPA pathway in the pathogenesis of pain in various disease states.
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Introduction Osteoarthritis (OA) is a degenerative joint disorder that involves progressive changes in all joint structures initiated by a combination of mechanical, genetic and age-associated factors [1], [2], [3]. Other risk factors associated with OA include gender, obesity, poor nutrition, and muscle weakness [3]. Despite the etiology of OA being unclear, Temsirolimus has been strongly associated with the destruction of extracellular matrix resulting in the softening and degradation of cartilage tissue, remodeling of subchondral bone, and increased bone vascularization, accompanied by the clinical symptoms of the disease including pain, joint swelling, early morning stiffness, and disability [4], [5]. Radiographic examination can reveal key pathological features including joint space narrowing, as the result of the loss of articular cartilage, and abnormalities in bone structure for example osteophyte formation, subchondral sclerosis, and subchondral bone cyst [6]. Autotaxin (ATX) or ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP)-2 is a 125kDa glycoprotein that belongs to the ENPP family [7]. It is secreted as lysophospholipase D (lysoPLD), an active enzyme with a distinct catalytic domain able to hydrolyze lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA) and choline [8]. Abundant concentrations of LPA can be detected in biological fluids including serum, synovial fluid, and plasma. Serum is the best characterized source of LPA [9] and studies have shown that the majority of circulating LPA is produced by the lysoPLD activity of autotaxin [10], [11], [12], [13]. LPA initiates and mediates a variety of cellular signaling pathways by binding to six cell surface-expressed guanine-nucleotide-binding protein (G-protein)-coupled receptors named LPA1–6[14]. Previous studies have highlighted that local LPA production plays a critical role in stimulating cell proliferation, migration, and cytokine and matrix metalloproteinase (MMP) production in chronic inflammatory diseases including rheumatoid arthritis (RA) [9]. Increased expression of autotaxin mRNA detected in synovial fibroblasts (SFs) of arthritic mouse models can lead to local LPA production and subsequent LPA-dependent SF stimulation [15]. This leads to increased cellular adhesion, migration, and enhanced production of pro-inflammatory cytokines and MMPs [15]. SFs isolated from OA patients were shown to express significant amounts of autotaxin mRNA [15]. Furthermore, expression of LPA 1–3 has been observed in human OA SFs [16], suggesting a potential role of autotaxin and LPA signaling in the pathogenesis of OA.