Abstract
Background:Stem cell therapies can be a new therapeutic strategy that may rebalance anabolic and anti-resorptive effects in osteoporosis patients. Tonsil-derived mesenchymal stem cells (TMSCs) can be an alternative therapeutic source for chronic degenerative diseases including osteoporosis. MSCs acquire immune regulatory function under the inflammatory cytokines. Since interleukin (IL) 1β is known to be one of inflammatory cytokines involved in osteoporosis progression, treatment of IL1β with TMSCs may enhance immunomodulatory function and therapeutic effects of TMSCs in osteoporosis.Methods:For IL1β priming, TMSCs were cultured in the presence of the medium containing IL1β for 1 day. Characteristics of IL1β priming TMSCs such as multipotent differentiation properties, anti-inflammatory potential, and suppression of osteoclast differentiation were assessed in vitro. For in vivo efficacy study, IL1β priming TMSCs were intravenously infused twice with ovariectomized (OVX) osteoporosis mouse model, and blood serum and bone parameters from micro computed tomography images were analyzed.Results:IL1β priming TMSCs had an enhanced osteogenic differentiation and secreted factors that regulate both osteoclastogenesis and osteoblastogenesis. IL1β priming TMSCs also suppressed proliferation of peripheral blood mononuclear cells (PBMCs) and decreased expression of Receptor activator of nuclear factor kappa-Β ligand (RANKL) in PHA-stimulated PBMCs. Furthermore, osteoclast specific genes such as Nuclear factor of activated T cells c1 (NFATc1) were effectively down regulated when co-cultured with IL1β priming TMSCs in RANKL induced osteoclasts. In OVX mice, IL1β priming TMSCs induced low level of serum RANKL/osteoprotegerin (OPG) ratio on the first day of the last administration. Four weeks after the last administration, bone mineral density and serum Gla-osteocalcin were increased in IL1β priming TMSC-treated OVX mice. Furthermore, bone formation and bone resorption markers that had been decreased in OVX mice with low calcium diet were recovered by infusion of IL1β priming TMSCs.Conclusion:IL1β priming can endow constant therapeutic efficacy with TMSCs, which may contribute to improve bone density and maintain bone homeostasis in postmenopausal osteoporosis. Therefore, IL1β priming TMSCs can be a new therapeutic option for treating postmenopausal osteoporosis.
Highlights
Osteoporosis is a systemic bone disease characterized by reduced bone density and deterioration of micro-architecture of bone tissue
Our preliminary RNAseq analysis showed that pro-osteogenic transcription factors and signaling factors such as RUNX2 (1.48 fold), TWIST 2 (1.79 fold), IGF2 (3.5 fold), BMP2 (12.66 fold), BMP7 (6.55 fold), WNT10A (2.03 fold), and WNT16 (2.88 fold) were differentially increased in IL1b priming Tonsil-derived mesenchymal stem cells (TMSCs) compared to mock control (Data not shown)
16 weeks after ovariectomy, both bone formation marker, Gla-osteocalcin, and bone resorption marker, CTX-1, were reduced in vehicle-treated OVX mice compared to Corresponding to the serum analyses, protein levels of both bone formation marker (RUNX2 and osteocalcin) and resorption maker were recovered in whole bone tissue of IL1b priming TMSC-treated OVX mice (Fig. 5E). These results suggested that IL1b priming TMSCs have potential to restore bone homeostasis in osteoporosis
Summary
Osteoporosis is a systemic bone disease characterized by reduced bone density and deterioration of micro-architecture of bone tissue. Stem cell therapies can be a new therapeutic strategy that may rebalance anabolic and anti-resorptive effects in osteoporosis patients. For in vivo efficacy study, IL1b priming TMSCs were intravenously infused twice with ovariectomized (OVX) osteoporosis mouse model, and blood serum and bone parameters from micro computed tomography images were analyzed. Four weeks after the last administration, bone mineral density and serum Gla-osteocalcin were increased in IL1b priming TMSC-treated OVX mice. Bone formation and bone resorption markers that had been decreased in OVX mice with low calcium diet were recovered by infusion of IL1b priming TMSCs. CONCLUSION: IL1b priming can endow constant therapeutic efficacy with TMSCs, which may contribute to improve bone density and maintain bone homeostasis in postmenopausal osteoporosis. IL1b priming TMSCs can be a new therapeutic option for treating postmenopausal osteoporosis
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