Abstract
Cajanolactone A (CLA) is a stilbenoid discovered by us from Cajanus cajan (L.) Millsp. In our study, CLA was found to promote osteoblast differentiation in human bone marrow mesenchymal stem cells (hBMSCs), as judged by increased cellular alkaline phosphatase activity and extracellular calcium deposits, and elevated protein expression of Runx2, collagen-1, bone morphogenetic protein-2, and osteopontin. Mechanistic studies revealed that hBMSCs undergoing osteoblast differentiation expressed upregulated mRNA levels of Wnt3a, Wnt10b, LRP5/6, Frizzled 4, β-catenin, Runx2, and Osterix from the early stage of differentiation, indicating the role of activated Wnt/β-catenin signaling pathway in osteoblast differentiation. Addition of CLA to the differentiation medium further increased the mRNA level of Wnt3a, Wnt10b, Frizzled 4, LRP5, and β-catenin, inferring that CLA worked by stimulating Wnt/LRP5/β-catenin signaling. Wnt inhibitor dickkopf-1 antagonized CLA-promoted osteoblastogenesis, indicating that CLA did not target the downstream of canonical Wnt signaling pathway. Treatment with CLA caused no changes in mRNA expression level, as well as protein secretion of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL), indicating that CLA did not affect the OPG/RANKL axis. Our results showed that CLA, which promoted osteoblast differentiation in hBMSCs, through activating Wnt/LRP5/β-catenin signaling transduction, is a promising anti-osteoporotic drug candidate.
Highlights
Wnt/β-catenin signaling pathway, known as the canonical Wnt signaling pathway, plays a key role in the differentiation of bone marrow mesenchymal stem cell (BMSC) into osteoblast and regulates osteoblast function, from initial fate determination to its maturation [1]
Cajanolactone A did not Stimulate the Proliferation of human bone marrow mesenchymal stem cells (hBMSCs)
The effect of cajanolactone A (CLA) (Figure 1A) or on72proliferation of hBMSCs was and, firstly at μM, it even exhibited an inhibitory effect on cell proliferation
Summary
Wnt/β-catenin signaling pathway, known as the canonical Wnt signaling pathway, plays a key role in the differentiation of bone marrow mesenchymal stem cell (BMSC) into osteoblast and regulates osteoblast function, from initial fate determination to its maturation [1]. In our previous fraction from the leaves of was reported to promote the proliferation ofinvestigation, BMSCs and abehydrophobic beneficial to clinical applications of C. cajan showed ability tohead increase density in diabetic/obese mice [13].fraction. A, and cajanolactone the leaves of C. cajan showed ability to increase tibial bone density in diabetic/obese mice A,. Stilbenoids, cajanstilbene cajanonic acid A, and activity [15], while cajanonic acid A by showed therapeutic potential the treatmentHofexhibited type 2 diabetes cajanolactone. A promoted osteoblast osteogenesis-promoting activity [15], while cajanonic acid A showed therapeutic potential in the differentiation mesenchymal cells findings (hBMSCs) stimulating A treatment of typein human diabetesbone [16]. Wnt/LRP5/β-catenin signaling, and is a promising anti-osteoporotic drug candidate. Promoted osteoblast differentiation in human bone marrow mesenchymal stem cells (hBMSCs) via stimulating Wnt/LRP5/β-catenin signaling, and is a promising anti-osteoporotic drug candidate
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