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Abstract
Multinucleation of osteoclasts during osteoclastogenesis requires dynamic rearrangement of the plasma membrane and cytoskeleton, and this process involves numerous previously characterized factors. However, the mechanism underlying osteoclast fusion remains obscure. Live-imaging analysis of osteoclastogenesis revealed that the products of PI3-kinase are enriched at the sites of osteoclast fusion. Among the downstream molecules whose expression was screened, the expression of Tks5, an adaptor protein with the phox homology (PX) domain with multiple Src homology 3 domains, was induced during osteoclastogenesis. Tks5 was localized in the podosomes and fusing membranes of osteoclasts, and reducing its expression impaired both formation of circumferential podosomes and osteoclast fusion without altering osteoclast differentiation. In addition, the expression of a deletion mutant of the PX domain abrogated circumferential podosome formation as well as osteoclast fusion, suggesting that Tks5-dependent circumferential podosomes function as fusion machinery during osteoclastogenesis. As Tks5 is known to promote the formation of podosomes/invadopodia in transformed/cancer cells, we tested if these cells also have the potential to fuse with osteoclasts. Among the cells tested, B16F0 melanoma cells formed circumferential podosomes with Tks5 accumulation in the presence of RANKL, TGFβ and TNFα. Co-culture of B16F0 melanoma cells with osteoclasts in an inflammatory milieu promoted increased formation of melanoma-osteoclast hybrid cells. Our results revealed a previously unknown mechanism of regulation of both circumferential podosome formation and cell-cell fusion by Tks5.
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.clinical presentation and lesions evidenced by magnetic resonance imaging may be similar
After stimulation with anti-Fas mAb combined with TNFalpha, there was a citotoxic effect on healthy (p < 0,001 at 10, 100, 1000 ng/ml anti-Fas mAb), rheumatoid arthritis (RA) (p < 0,001 for any dose) and Haemophilic arthropathy (HA) synoviocytes (p < 0,005 at 1, 10, 100 and 1000 ng/ml anti-Fas mAb)
After stimulation with anti-Fas mAb combined with FGF, there was a citotoxic effect on healthy, RA and HA
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.clinical presentation and lesions evidenced by magnetic resonance imaging may be similar. 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]. In all probability, smoking induces expression or post-translational modification of immune activating proteins which initiate an autoimmune reaction in individuals with a susceptible genetic background To identify these triggering molecules we screened joints of mice that were exposed to cigarette smoke for differences of gene expression and verified our results in synovial tissues of human smokers. In this study we sought to identify novel miR associations in synovial fibroblasts (SFs), a key pathogenic cell type in RA [10,11], by performing miR expression profiling on cells isolated from the human TNF transgenic mouse model (TghuTNF, Tg197) [12] and patients biopsies. The objective of our study is to determine the association between autoantibodies expression, Th1/Th2 cytokines balance and IFNG polymorphisms with pathologic class of LN in Javanese patients
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