title: Factors secreted from dental pulp stem cells show multifaceted benefits for treating experimental rheumatoid arthritis.
abstract: Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and chronic inflammation, which lead to the progressive destruction of cartilage and bone in the joints. Numerous studies have reported that administrations of various types of MSCs improve arthritis symptoms in animal models, by paracrine mechanisms. However, the therapeutic effects of the secreted factors alone, without the cell graft, have been uncertain. Here, we show that a single intravenous administration of serum-free conditioned medium (CM) from human deciduous dental pulp stem cells (SHED-CM) into anti-collagen type II antibody-induced arthritis (CAIA), a mouse model of rheumatoid arthritis (RA), markedly improved the arthritis symptoms and joint destruction. The therapeutic efficacy of SHED-CM was associated with an induction of anti-inflammatory M2 macrophages in the CAIA joints and the abrogation of RANKL expression. SHED-CM specifically depleted of an M2 macrophage inducer, the secreted ectodomain of sialic acid-binding Ig-like lectin-9 (ED-Siglec-9), exhibited a reduced ability to induce M2-related gene expression and attenuate CAIA. SHED-CM also inhibited the RANKL-induced osteoclastogenesis in vitro. Collectively, our findings suggest that SHED-CM provides multifaceted therapeutic effects for treating CAIA, including the ED-Siglec-9-dependent induction of M2 macrophage polarization and inhibition of osteoclastogenesis. Thus, SHED-CM may represent a novel anti-inflammatory and reparative therapy for RA.
authors.affiliation: Department of Oral and Maxillofacial Surgery, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ishikawa
authors.affiliation: Orthopedic Surgery and Rheumatology, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Nobunori
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Orthopedic Surgery and Rheumatology, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Orthopedic Surgery and Rheumatology, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshioka
authors.affiliation: Department of Oral and Maxillofacial Surgery, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Oral and Maxillofacial Surgery, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Nishikawa
authors.affiliation: Department of Oral and Maxillofacial Surgery, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Hideharu
authors.initials: H
authors.lastname: Hibi
authors.affiliation: Orthopedic Surgery and Rheumatology, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishigro
authors.affiliation: Department of Oral and Maxillofacial Surgery, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Biochemistry II of Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Furukawa
authors.affiliation: Department of Oral and Maxillofacial Surgery, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: akihito@med.nagoya-u.ac.jp.
authors.forename: Akihito
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000906:Antibodies; D015703:Antigens, CD / Q000378:metabolism; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology*; D002648:Child; D024043:Collagen Type II / Q000276:immunology; D017077:Culture Media, Conditioned / Q000737:chemistry; D003782:Dental Pulp / Q000166:cytology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D007275:Injections, Intravenous; D007596:Joints / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D000906:Antibodies; D015703:Antigens, CD; D024043:Collagen Type II; D017077:Culture Media, Conditioned; C412227:SIGLEC9 protein, human; D063265:Sialic Acid Binding Immunoglobulin-like Lectins
keywords: Conditioned medium; Dental pulp stem cells; Inflammation; Macrophages; Osteoclasts; Rheumatoid arthritis