Pamidronate regulates the osteogenic differentiation of periosteal-derived mesenchymal stem cells in congenital tibial pseudarthrosis via OPG/RANKL.

BACKGROUND

Congenital pseudarthrosis of the tibia (CPT) is one of the most challenging conditions in orthopedics. Previous research indicates a strong association between CPT and neurofibromatosis type 1 (NF1). The clinical application of pamidronate has demonstrated efficacy in enhancing bone healing and alleviating NF1-associated bone pathology in specific CPT cases. Nevertheless, the precise mechanistic basis for these therapeutic effects remains poorly characterized, warranting further investigation.

METHODS

In this study, mesenchymal stem cells (MSCs) were isolated from patients with congenital pseudarthrosis of the tibia (CPT MSCs) and from patients undergoing corrective osteotomy (control group). We examined cell conditions post-treatment with pamidronate disodium at concentrations of 0 nM, 10 nM, 100 nM, and 1 μM, evaluating proliferation, toxicity, and differentiation potential, while investigating its effects on the OPG/RANKL pathway. Additionally, we analyzed the alterations in mitogen-activated protein kinase signaling and its correlation with the regulatory expression of OPG/RANKL genes.

RESULTS

This study demonstrated that the proliferation and osteogenic differentiation of CPT MSCs were significantly lower than those of the control group. Treatment with pamidronate disodium enhanced both proliferation and osteogenic differentiation in CPT MSCs. Furthermore, pamidronate disodium treatment decreased RANKL expression and increased OPG protein levels in CPT MSCs, activating p38 and ERK1/2 signaling pathways. Notably, the co-administration of p38 or ERK1/2 inhibitors significantly diminished the proliferation and osteogenic differentiation of CPT MSCs treated with pamidronate disodium.

CONCLUSION

Pamiphosphonate disodium can promote the proliferation and osteogenic differentiation of CPT MSCs by activating p38 and ERK1/2 signaling.