It has been widely accepted that regenerative medicine including stem cell therapy and tissue engineering offers a huge potential technique to whole organ and tissue transplantation for diseased, failed or malfunctioned organs. There were already launched eighteen products in market after the approval of KFDA. However, these products were more developed cell therapy products rather than tissue engineered products. To reconstruct a new tissue by tissue engineering, three basic components such as (1) primary/stem cells, (2) biomaterials as scaffold substrates and (3) growth factors must be needed.
Among of these three key components, scaffolds as biomaterials might be played a very critical role in tissue engineered products. The function of scaffolds is to direct the growth of cells seeded within the porous structure of the scaffold or of cells migrating from surrounding tissue, eventually mimicking a natural extracellular matrix. For the scaffold materials, the family of poly(α-hydroxy acid)s are extensively clinically used or tested due to good biocompatibility, controllable biodegradabilitiy, and relatively good processability. The main reasons of the retard of FDA approval for tissue engineered products might be the induction of inflammation reaction in terms of safety. In our laboratory, we have been investigated the reduction of inflammation reaction of poly(α-hydroxy acid)s by the hybridization with natural biomaterials. In this review, poly(α-hydroxy acid)s/natural hybrid scaffold biomaterials have been introduced in order to reduce the host response resulting in approaching to a more natural three dimensional environment and supporting biological signals for tissue growth and reorganization of organ.

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Rheumatoid arthritis (RA) is a common autoimmune inflammatory disease causing bone destruction. Although the etiology of RA remains unanswered, it is well known that inflammatory cytokines play key roles. Although biological agents targeting these inflammatory cytokines strongly suppress inflammation as well as bone damages, repair of destructed bone is still challenging. Mesenchymal stem cells (MSCs) are capable to differentiate into osteoblasts and chondrocytes and moreover, they have been reported to possess immunomodulative effects without severe adverse events in patients with graft versus host disease. Recently, we have reported that MSCs produce osteoprotegerin (OPG), a decoy receptor of the receptor activator of NFκB ligand (RANKL) resulting in reduced osteoclastogenesis. We herein demonstrate the promotive effect of inflammatory cytokines on osteoblast differentiation through Wingless-type MMTV integration site family (Wnt) 5a/ receptor tyrosine kinase-like orphan receptor (Ror) 2 signaling pathway. Our results suggest that MSCs is a powerful treatment tool for RA patients to aim suppression of inflammation and bone regeneration in parallel.

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Adipokines are cytokines secreted from adipocytes. They play an essential role in both metabolic diseases and inflammatory diseases such as rheumatoid arthritis (RA). In RA patients, concentrations of typical adipokines in the synovial fluid or serum tend to be higher than in control subjects; therefore, the role of adipokines in inflammation has been under intense investigation. Adiponectin (Ad) in particular plays a role in many biological processes, however, its influence on inflammation is controversial. From our investigations into how Ad may act in inflammation we concluded that infiltrating macrophages and neutrophils at sites of local inflammation, such as in the synovial tissues of RA patients, are activated by inflammatory cytokines and secrete elastase resulting in the production of globular Ad (gAd), and that that gAd augments the inflammatory response.

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The biology of fibroblast-like cells is important in understanding of pathogeneis of rheumatoid arthritis (RA). Fibroblast-like synovial cells (FLSs) is major component of pannus in inflamed joint, and mesenchymal stromal cells (MSCs) is thought to be in bone edema, a recently reported RA lesion in bone marrow that is detectable by MRI. It is interesting that MSCs share many characteristics with FLSs. Both types of cells can secrete cytokines, and differentiate into mesenchymal lineage cells such as osteoblasts, chondrocytes, and adipocytes. In this review, we discuss the possible contribution of the adipogenesis insufficency of FLSs or MSCs to the development of synovial hyperplasia and bone edema in RA.

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Photoreceptor cells receive light and transduce it to electrical signals for visual perception. However, excessive exposure to visible light causes photoreceptor cells to undergo apoptosis, which is called photo-damage. This damage involves several biochemical events, including the accumulation of oxidative stress and the elevation of intracellular calcium and nitric oxide (NO). Photo-damage is thought to be related to the progression of retinitis pigmentosa and age-related macular degeneration. Therefore, understanding the molecular mechanisms of retinal photo-damage using model animals may lead to new therapeutic approaches for preventing the progression of these ocular diseases. In this review, we summarize previous reports examining the mechanisms of light-induced retinal damage, and briefly describe the interventional effect of lutein against photo-damage in mice. Lutein is taken from food and systemically delivered to the retina, skin, and certain organs and tissues. It reduces the level of reactive oxygen species and acts as an anti-oxidant in the retina of light-exposed mice, ultimately preventing light-induced DNA double-strand breaks and apoptosis. Although further study is required, lutein may be proposed as a new therapeutic approach for preventing photo-damage in humans.

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A new type of glycolipid, phosphatidylglucoside (PtdGlc), first identified as a component of lipid rafts in the human HL-60 leukemia cell line, has also been detected in human neutrophils during maturation. We show here that PtdGlc forms functional domains different from lactosylceramide (LacCer)-enriched lipid rafts and initiates neutrophil apoptosis via Fas-dependent death signaling. Among the human peripheral blood leukocytes and monocyte-derived dendritic cells (DCs), only neutrophils show high surface expression of PtdGlc, whereas LacCer is expressed on the surfaces of neutrophils, macrophages and DCs. LacCer couples with the Src family kinase Lyn, forming lipid rafts on plasma membranes, and mediates neutrophil chemotaxis, phagocytosis and superoxide generation, whereas PtdGlc does not mediate these functions. In contrast, PtdGlc but not LacCer is involved in neutrophil apoptosis. These observations suggest that PtdGlc and LacCer form distinct lipid domains on the plasma membrane. In addition, PtdGlc-mediated apoptosis was inhibited by specific inhibitors of caspases 8, 9 and 3, but not by the Src family kinase inhibitor PP1, the PI3 kinase inhibitor LY294002 or catalase. PtdGlc colocalized with Fas on neutrophil plasma membranes, and both the anti-PtdGlc antibody DIM21 and the agonist anti-Fas antibody B-10 induced the formation of large Fas-colocalized clusters of PtdGlc on plasma membranes. Furthermore, the antagonist anti-Fas antibody ZB4 significantly inhibited DIM21-induced neutrophil apoptosis. These results suggest that PtdGlc is specifically expressed on neutrophils and mediates activities of these cells, and that the Fas-associated death signal may be involved in PtdGlc-mediated apoptosis.

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The lysosome is an acidic compartment containing certain hydrolytic enzymes necessary for the intracellular digestion of macromolecules. In terms of the activity of bone-resorbing osteoclasts, the secretion of lysosomal vesicles containing protons and matrix-degrading proteinases into the resorption lacunae is essential. Chloroquine (CQ), one of the lysosomotropic agents, has an immunosuppressive effect and is used for the treatment for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, the direct effect of CQ on osteoclasts has not been reported. Here, we show that CQ suppresses the bone resorbing activity of osteoclasts by inhibition of the acidification in the lysosomes, as well as osteoclast differentiation in vitro. CQ treatment ameliorates the bone loss induced by RANKL injection in mice. These results suggest that CQ has a bone-increasing effect by inhibiting osteoclast differentiation and function. In addition, a lysosomal proton pump inhibitor bafilomycin A1 also inhibits osteoclast differentiation. Thus, this study revealed the importance of the lysosomes in osteoclast differentiation and function in vivo as well as in vitro, suggesting the therapeutic efficacy of immunosuppressive CQ in osteoclast-mediated bone loss or destruction.

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