Transplantation of mesenchymal stem cells ameliorates secondary osteoporosis through interleukin-17-impaired functions of recipient bone marrow mesenchymal stem cells in MRL/lpr mice.

Yosuke Tanaka,Takayoshi Yamaza,Haruyoshi Yamaza,Erika Tomoda,Kazuaki Nonaka,Songtao Shi,Guangtai Song,Yoshihiro Hoshino,Reona Aijima,Lan Ma,Wei Zhao,Soichiro Sonoda

doi:10.1186/s13287-015-0091-4

Abstract

IntroductionSecondary 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.MethodsThe 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.ResultsSystemic 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.ConclusionsThese findings indicate that IL-17 and recipient BMMSCs might be a therapeutic target for secondary osteoporosis in systemic lupus erythematosus.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0091-4) contains supplementary material, which is available to authorized users.

Highlights

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
bone marrow cell (BMC)-human bone marrow mesenchymal stem cell (hBMMSC) and BMC-stem cells from human exfoliated deciduous teeth (SHED) exhibited lower production of IL-17 than BMC-MRL/lpr, as well as BMC-Pre-MRL/lpr (Fig. 2f ), reflecting the recipient bone marrow IL-17 conditions. These findings indicated that transplanted hBMMSCs and SHED might suppress the abnormal IL-17 production in the recipient bone marrow of MRL/lpr mice, but did not evaluate whether the recipient IL-17 conditions effected on the dysregulation by osteoclastic bone resorption and osteoblastic bone formation in MRL/lpr mice
Anti-IL-17 antibody treatment completely neutralized the IL-17suppressed osteogenic capacities of mesenchymal stem cell (MSC)-hBMMSC and MSC-SHED (Fig. 3d). These findings indicated that abnormal IL-17 in the bone marrow of MRL/lpr mice impaired the osteogenic capacity of recipient bone marrow mesenchymal stem cell (BMMSC), and suggested that hBMMSC and SHED transplantation recovered the osteogenic dysfunction of recipient BMMSCs through inhibiting hyperactivated IL-17 in the recipient bone marrow of MRL/lpr

Summary

Introduction

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. 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. Because recent medical advances have successfully increased the lifespan of patients with SLE, many clinical researchers have focused on the organ damage associated with the systemic chronic inflammation and/or long-term medications relating to quality of life [3]. There are no safe or efficient treatments for SLE-associated osteoporosis

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Conclusion