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

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

Secondary osteoporosis is common in systemic lupus erythematosus (SLE) and leads to the loss of quality of life by fragility fractures, even in patients with improvement of the primary disorder. Systemic transplantation of mesenchymal stem cells (MSCs) could ameliorate bone loss and autoimmune disorders in SLE model MRL/lpr mice, but the detailed therapeutic mechanism of bone regeneration is not fully understood. In this study, we transplanted human bone marrow MSCs (BMMSCs) and stem cells from exfoliated deciduous teeth (SHED) into MRL/lpr mice and explored their therapeutic mechanisms in secondary osteoporotic disorders of SLE model mice. Effects of systemic human MSC transplantation on the bone loss of MRL/lpr mice were analyzed in vivo and ex vivo. After systemic human MSC transplantation, recipient BMMSCs functions of MRL/lpr mice were assessed for stemness, osteogenesis and osteoclastogenesis aspects and a series of co-culture experiments under osteogenic or osteoclastogenic inductions were performed to examine the efficacy of Interleukin 17 (IL-17)-impaired recipient BMMSC in the bone marrow of MRL/lpr mice. Systemic transplantation of human BMMSCs and SHED recovered the reduction of bone density and structures 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 condition 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 then maintained a regular positive bone metabolism via the balance of osteoblasts and osteoclasts. These findings indicate that IL-17 and recipient BMMSCs might be a therapeutic target of secondary osteoporosis in SLE.