title: Transplantation of mesenchymal stem cells ameliorates secondary osteoporosis through interleukin-17-impaired functions of recipient bone marrow mesenchymal stem cells in MRL/lpr mice.
abstract: BACKGROUND
  Secondary osteoporosis is common in systemic lupus erythematosus and leads to a reduction in quality of life due to fragility fractures, even in patients with improvement of the primary disorder. Systemic transplantation of mesenchymal stem cells could ameliorate bone loss and autoimmune disorders in a MRL/lpr mouse systemic lupus erythematosus model, but the detailed therapeutic mechanism of bone regeneration is not fully understood. In this study, we transplanted human bone marrow mesenchymal stem cells (BMMSCs) and stem cells from exfoliated deciduous teeth (SHED) into MRL/lpr mice and explored their therapeutic mechanisms in secondary osteoporotic disorders of the systemic lupus erythematosus model mice.
  
  
  METHODS
  The effects of systemic human mesenchymal stem cell transplantation on bone loss of MRL/lpr mice were analyzed in vivo and ex vivo. After systemic human mesenchymal stem cell transplantation, recipient BMMSC functions of MRL/lpr mice were assessed for aspects of stemness, osteogenesis and osteoclastogenesis, and a series of co-culture experiments under osteogenic or osteoclastogenic inductions were performed to examine the efficacy of interleukin (IL)-17-impaired recipient BMMSCs in the bone marrow of MRL/lpr mice.
  
  
  RESULTS
  Systemic transplantation of human BMMSCs and SHED recovered the reduction in bone density and structure in MRL/lpr mice. To explore the mechanism, we found that impaired recipient BMMSCs mediated the negative bone metabolic turnover by enhanced osteoclastogenesis and suppressed osteoblastogenesis in secondary osteoporosis of MRL/lpr mice. Moreover, IL-17-dependent hyperimmune conditions in the recipient bone marrow of MRL/lpr mice damaged recipient BMMSCs to suppress osteoblast capacity and accelerate osteoclast induction. To overcome the abnormal bone metabolism, systemic transplantation of human BMMSCs and SHED into MRL/lpr mice improved the functionally impaired recipient BMMSCs through IL-17 suppression in the recipient bone marrow and then maintained a regular positive bone metabolism via the balance of osteoblasts and osteoclasts.
  
  
  CONCLUSIONS
  These findings indicate that IL-17 and recipient BMMSCs might be a therapeutic target for secondary osteoporosis in systemic lupus erythematosus.
authors.affiliation: Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. malan2010@dent.kyushu-u.ac.jp.|Department of Pediatric Dentistry, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. malan2010@dent.kyushu-u.ac.jp.|Department of Pediatric Dentistry, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, No. 56, Lingyuan Xi Road, Guangzhou, 510055, China. malan2010@dent.kyushu-u.ac.jp.
authors.forename: Lan
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. leona@dent.kyushu-u.ac.jp.
authors.forename: Reona
authors.initials: R
authors.lastname: Aijima
authors.affiliation: Department of Pediatric Dentistry, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. yoshi2@dent.kyushu-u.ac.jp.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hoshino
authors.affiliation: Department of Pediatric Dentistry, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. hyamaza@dent.kyushu-u.ac.jp.
authors.forename: Haruyoshi
authors.initials: H
authors.lastname: Yamaza
authors.affiliation: Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. tomoda.erika.899@s.kyushu-u.ac.jp.|Department of Pediatric Dentistry, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. tomoda.erika.899@s.kyushu-u.ac.jp.
authors.forename: Erika
authors.initials: E
authors.lastname: Tomoda
authors.affiliation: Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. 3dd14001y@s.kyushu-u.ac.jp.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. ilikeanimalaso@gmail.com.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Sonoda
authors.affiliation: Department of Pediatric Dentistry, School of Stomatology, Wuhan University, Luo-jia-shan, Wuchang, Wuhan, 430072, China. gtsong@vip.sina.com.
authors.forename: Guangtai
authors.initials: G
authors.lastname: Song
authors.affiliation: Department of Pediatric Dentistry, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, No. 56, Lingyuan Xi Road, Guangzhou, 510055, China. zhaowei3@mail.sysu.edu.cn.|Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, No. 135, Xingang Xi Road, Guangzhou, 510275, China. zhaowei3@mail.sysu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Pediatric Dentistry, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. nonaka@dent.kyushu-u.ac.jp.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nonaka
authors.affiliation: Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry of USC, University of Southern California, 2250 Alcazar Street, Los Angeles, CA, 90033-9062, USA. songtaos@usc.edu.|Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, 240 South 40th Street, Philadelphia, PA, 19204-6030, USA. songtaos@usc.edu.
authors.forename: Songtao
authors.initials: S
authors.lastname: Shi
authors.affiliation: Department of Molecular Cell Biology and Oral Anatomy, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. yamazata@dent.kyushu-u.ac.jp.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Yamaza
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D018920:Coculture Techniques; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000473:pathology; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000628:therapy; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D010012:Osteogenesis / Q000187:drug effects; D010024:Osteoporosis / Q000150:complications / Q000628:therapy*; D011859:Radiography; D012886:Skull / Q000166:cytology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D000906:Antibodies; D020381:Interleukin-17