Pamidronate Disodium Leads to Bone Necrosis via Suppression of Wnt/β-Catenin Signaling in Human Bone Marrow Mesenchymal Stem Cells In Vitro

Yan Xu, Jin Sun, Xuewen Yang, Yuehai Yu, Huijing Mai, Zubing Li
Journal of Oral and Maxillofacial Surgery 2017, 75 (10): 2135-2143

PURPOSE: Pamidronate disodium-associated bone necrosis is poorly understood at the cellular and molecular levels. This study proposes a pathway leading to the pamidronate disodium-mediated inhibition of osteogenic differentiation of human bone marrow mesenchymal stem cells (BMMSCs) derived from the mandible in vitro.

MATERIALS AND METHODS: Primary human BMMSCs were isolated from the mandible and marrow tissue. A proliferation assay was performed to determine the experimental concentration of pamidronate disodium. Alkaline phosphatase (ALP) activity, ALP staining, and Alizarin red S (ARS) staining were assessed after treatment with pamidronate disodium (0, 0.1, 0.5, 1, 5, 10 μg/mL). Quantitative real-time polymerase chain reaction and western blotting specific for Wnt and β-catenin signaling genes or proteins were performed after treatment with pamidronate disodium 0.5 μg/mL. Wnt3a was used to observe the osteogenic differentiation of BMMSCs during treatment with pamidronate disodium 0.5 μg/mL.

RESULTS: As expected, pamidronate disodium 1, 5, and 10 μg/ml were unfavorable for BMMSC growth (P < .05), whereas 0.1 and 0.5 μg/mL did not affect BMMSC growth (P ≥ .05). BMMSCs treated with pamidronate disodium 0.5 μg/mL had lower ALP activity, ALP staining, and ARS staining (P < .05), and BMMSCs treated with low concentrations (<0.5 μg/mL) of pamidronate disodium had the same levels of ALP activity, ALP staining, and ARS staining as the control (0 μg/mL). Pamidronate disodium 0.5 μg/mL decreased the expression of genes and proteins involved in Wnt and β-catenin signaling. BMMSCs with Wnt3a and pamidronate disodium 0.5 μg/mL had higher ALP activity, ALP staining, and ARS staining (P < .05).

CONCLUSIONS: Pamidronate disodium inhibited Wnt and β-catenin signaling, which controls osteogenic differentiation in BMMSCs. Wnt3a, a Wnt and β-catenin signaling activator, reversed the negative effects caused by pamidronate disodium to salvage the osteogenic defect in BMMSCs.

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