Influence of aminobisphosphonates on the osteogenic potential of bone marrow stromal cells (BMSCs) isolated from osteoporotic hip fracture patients

Introduction: Human bone marrow stromal cells (BMSCs) represent the precursor cells of bone-forming osteoblasts and have been shown to be functionally altered in age-related osteoporosis. The present study therefore sought to evaluate the effects of both aminobisphosphonate (amino-BP) in vitro and in vivo treatment on the osteogenic differentiation capacity and viability of human BMSCs obtained from aged female osteoporotic hip fracture patients. Methods: BMSCs were isolated from 7 osteoporotic patients without history of amino-BP medication and from 3 osteoporotic patients undergoing oral alendronate therapy. BMSCs were incubated in osteogenic and adipogenic medium supplemented with or without zoledronate (10 and 100 nM). The effect of amino-BP treatment on BMSC osteogenesis was assessed by qRT-PCR and Western blot analysis of known osteogenic markers. Mineralized matrix formation of differentiating BMSCs was quantified at days 14 and 21 of osteogenic induction using Alizarin Red S staining. Results: In vitro exposure to zoledronate during osteogenic differentiation significantly enhanced mineralization of differentiating BMSCs. Moreover, we could show that BMSCs from aged osteoporotic hip fracture patients undergoing oral alendronate therapy exhibited a greatly enhanced mineralization capacity as compared to BMSCs from osteoporotic controls not receiving amino-BP therapy. In vitro and in vivo treatment with amino- BPs had a marked inhibitory effect on secreted phosphoprotein 1 (SPP1) gene expression. Finally, loss-of-function studies confirmed that specific knockdown of SPP1 expression resulted in a marked increase in mineralization of osteoporotic BMSCs. Conlusion: The results presented within this thesis, provide evidence for an osteoanabolic effect of amino-BPs on osteoporotic BMSCs and implicate the amino- BP-induced downregulation of SPP1 as a possible mechanism of action.by Richard A. LindtnerAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersEnth. u.a. 1 Veröff. d. Verf. aus den Jahren 2013Innsbruck, Med. Univ., Diss., 2014OeBB(VLID)13282