Osteoinductive activity of bisdemethoxycurcumin and its synergistic protective effect with human amniotic mesenchymal stem cells against ovariectomy-induced osteoporosis mouse model

Abstract

Osteoporosis is a common disease characterized by skeletal fragility and microarchitectural deterioration. However, existing conventional drugs exhibit limited efficacy and can elicit severe adverse effects; moreover, and novel stem cell-based therapies have not exhibited sufficient therapeutic efficacy. Our hypothesis is that an appropriate osteogenic inducer may improve their therapeutic efficacy. In this study, we found that bisdemethoxycurcumin (BDMC) stimulates the differentiation of human amniotic mesenchymal stem cells (hAMSCs) into osteoblasts without inducing cytotoxicity. Here BDMC enhances calcium deposition in hAMSCs, while promoting the expression of early and late markers of osteoblast differentiation, including ALP, runt-related transcription factor 2, osterix, COL1-α1, osteocalcin, and osteopontin at the transcriptional and translational levels. Mechanistically, BDMC was found to activate the JAK2/STAT3 pathway; whereas AG490 (JAK2/STAT3 pathway inhibitor) inhibited BDMC functioning. Subsequently, we found that the combinatorial therapy of BDMC and hAMSC had a positive synergistic effect on osteoporotic mouse model induced by bilateral ovariectomy, including inhibiting bone loss and bone resorption and improving bone micro-architecture. Moreover, BDMC inhibited production of the bone resorption markers C-terminal telopeptide of type I collagen, and tartrate resistant acid phosphatase, while promoting serum levels of bone formation markers OCN, and procollagen I N-terminal propeptide. BDMC also improved liver and kidney function in osteoporotic mouse model. Collectively, BDMC improved osteoporosis by enhancing hAMSC osteogenesis and exhibited a protective effect on liver and kidney function in an osteoporotic mouse model. Hence, BDMC may serve as an effective adjuvant, and combined therapy with hAMSCs is a promising new approach toward osteoporosis treatment.

Keywords: Bisdemethoxycurcumin; Human amniotic mesenchymal stem cell; JAK2/STAT3 pathway; Osteoblast differentiation; Ovariectomy-induced osteoporosis; Synergistic effect.