In addition to the data
In addition to the data provided by the Ki16425 treatment in the K/BxN arthritis model, new findings from the study of two new LPA receptor antagonists confirm the involvement of the LPA pathway in the pathogenesis of experimental arthritis. In the study by Miyabe et al., the authors reported the treatment of mice with CIA using the specific LPA1 antagonist LA-01, which reduced the incidence and severity of arthritis, synovial inflammation and bone erosion. Additionally, the LPA analogue BrP-LPA acts as a pan-antagonist of LPA receptors and as an inhibitor of the lysophospholipase D activity of ATX. The treatment with BrP-LPA also reduced the incidence and severity of arthritis in mice injected with type II collagen (Nikitopoulou et al., 2013).
ATX–LPA pathway inhibitors ATX and LPA1 receptor have been involved in several pathological conditions besides rheumatoid arthritis, such as cancer, neuropathic pain, fibrotic diseases, etc. Development of ATX and LPA receptor inhibitors have been initiated some years ago with treatment of these diseases in mind. The early synthetic ATX inhibitors were lipid analogues of LPA or other lipids derived from the fact that LPA and S1P are feedback inhibitors of ATX. Later, screening of libraries led to discovery of new small-molecule leads such as the potent ATX inhibitor PF8380 which lead to a reduction of >95% of LPA in rat plasma. In addition, the boronic LDN-212854 derivatives were also potent ATX inhibitors. However, in our knowledge, no ATX inhibitor has reached clinical trials due to problems with in vivo stability and bioavailability. Regarding LPA receptor inhibitors, several LPA1/3 antagonists have been developed, among them, Ki16425, a potent LPA1/3 antagonist that reduced the induced renal fibrosis in mice (Pradère et al., 2007), the progression of bone metastasis in an experimental model (Boucharaba et al., 2006) and the severity of arthritis and bone erosion in mice (Orosa et al., 2012). Later, Debiopharm developed a R-stereoisomer of Ki16425, Debio 0719, which inhibited the formation of lung and bone metastases in a preclinical breast cancer mouse model (David et al., 2010). However, in our knowledge, neither these two compounds has entered yet clinical trials. More recently, Amira Pharmaceuticals has developed potent LPA1 selective antagonists that inhibit lung fibrosis in the mouse bleomycin model. In fact, one of these drugs acquired by Bristol-Myers Squibb is the first inhibitor (BMS-986020) of this pathway that is already in clinical trials (NCT 01766817) for the treatment of idiopathic pulmonary fibrosis. We hope that new ATX or LPA1 receptor antagonists with high potency and good pharmacological profile could reach clinical trials in RA and determine whether ATX–LPA pathway is a useful target in this disease.
Concluding remarks This review has summarised the intense research demonstrating the role of the ATX–LPA pathway in the pathogenesis of rheumatoid arthritis. Overall, data reviewed here point to ATX–LPA1 receptor pathway as a therapeutic target in this disease. Blocking ATX–LPA pathway could obtain clear therapeutic benefits involving multiple mechanisms, including reduction of FLS proliferation, cellular infiltration and sensitization of FLS to apoptosis, leading in turn, to reduction of synovial hyperplasia, key in the pathogenesis of rheumatoid arthritis. Other mechanisms include reduction of inflammatory mediators produced in the synovia and, very interestingly, a marked decrease of bone erosions that otherwise could lead to irreversible deformities and disability.
Conflict of interest
Acknowledgement The authors acknowledge the Instituto de Salud Carlos III, with the participation of the European Regional Development Fund of the European Union for their financial support (PI11/02197, RD12/0009/0008 (RIER)).
Production of LPA in cancer The first involvement of LPA in cancer emerged in the early 1990s through the detection of LPA in biopsies of colon tumors using magnetic resonance spectroscopy (MRS) whereas it was absent in biopsies from colons of healthy patients . Then, a further role was established for LPA in the initiation and progression of several cancers such as ovarian, prostate, breast, melanoma, thyroid and intestinal cancers . Increased LPA levels in the serum were found in patients with multiple myeloma . The relationship between tumor progression and LPA production is particularly well documented in ovarian cancers as the ascitic fluids of ovarian cancer patients contain 10 times higher concentrations of LPA (1–80µM) than those of healthy patients . Ovarian epithelial cells produce low levels of LPA, suggesting that most of LPA production may derive from the tumor cells themselves. This is supported by the observation that some ovarian cancer cell lines are capable of producing LPA in vitro . Moreover, LPA was shown acting in an autocrine manner on ovarian cancer cells by increasing its own production . Therefore, despite the fact that ovarian cancer cell lines do not express high levels of the LPA producing enzyme Autotaxin (ATX) mRNA, high tumor burden is frequently found in patients with ovarian cancers and as a consequence of a mass effect, low levels in ATX and LPA might be sufficient to induce a strong production of LPA in ascites and promote tumor development. In that respect LPA receptors, LPA2 and LPA3, that are overexpressed in most ovarian cancers may contribute to the LPA responsiveness of ovarian cancer cells , , . The level of circulating LPA has been proposed as a useful biological marker of tumor progression. Promising studies based on gas chromatography assays showed that LPA levels increased by 90% in the serum of patients with ovarian and other gynecologic cancers compared to physiological levels . However, mass spectrometry measurements did not find LPA variations in the plasma of patients with leukemia, ovarian and breast cancers . This descrepancy might be due to blood platelet activity that is known to be a main source of LPA in the blood circulation , . Platelet activity presents high inter-individual variations and platelet behavior is highly influenced by pharmacological drugs used in cancer therapies. As a consequence, the LPA level in blood is not useful in the clinic as a diagnotic or prognostic marker.