Mesenchymal stem cells from osteoporotic patients reveal reduced migration and invasion upon stimulation with BMP-2 or BMP-7

Abstract

Fractures to the osteoporotic bone feature a delay in callus formation and reduced enchondral ossification. Human mesenchymal stem cells (hMSC), the cellular source of fracture healing, are recruited to the fracture site by cytokines, such as BMP-2 and BMP-7. Aim of the study was to scrutinize hMSC for osteoporosis associated alterations in BMP mediated migration and invasion as well as in extracellular matrix (ECM) binding integrin expression. HMSC were isolated from 18 healthy or osteoporotic donors. Migration was assessed using a collagen IV coated micro-slide linear gradient chamber and time-lapse microscopy. Invasion was analyzed utilizing an ECM coated transmembrane invasion assay. Quantitative real-time RT PCR was performed for the ECM binding integrins α1, α2, α3, α4, α5, α11, αv and β1. HMSC from osteoporotic patients showed a significant increase of migration upon BMP-2 or FCS stimulation, as well as a significant increase of invasion upon BMP-2, BMP-7 or FCS stimulation. Nevertheless, the migration and invasion capacity was significantly decreased compared to healthy controls. Out of all integrins analyzed, collagen binding integrin α2 was significantly downregulated in hMSC from osteoporotic patients. In conclusion, we here demonstrate for the first time osteoporosis associated alterations in BMP mediated hMSC recruitment. These findings may underlie the reduced healing of osteoporotic fractures. Nevertheless, the maintained migration and invasion response upon BMP stimulation illustrates the therapeutic potential of these clinically approved substances in the treatment of osteoporotic fractures. Another therapeutic target may be the downregulation of the collagen binding integrin α2 in hMSC from osteoporotic patients.

The Role of Bone Marrow Microenvironment in Governing the Balance between Osteoblastogenesis and Adipogenesis

“…In such circumstances, the production of bone forming signaling molecules such as TGF-β1 and BMPs are reduced [60] whereas the production of their antagonists is increased [61]. Under such conditions, it is likely that the migration to bone forming surface and the subsequent osteoblastogenesis of MSCs are severely impaired [62,63].…”

Osteoporosis: the current status of mesenchymal stem cell-based therapy

“…BMPs function as both autocrine and paracrine factors, and their synthesis is induced by BMPs themselves via local feedback mechanisms. Evidence has shown that MSCs from osteoporosis patients are impaired in function and this alteration is associated with BMP signaling [95, 96]. However, BMP antagonists have been described, including noggin (NOG) and gremlin (GREM).…”

Osteoporosis and ageing affects the migration of stem cells and this is ameliorated by transfection with CXCR4

“…12 It has also been demonstrated that MSCs from osteoporotic humans have impaired migration towards chemo-attractants such as foetal calf serum (FCS), bone morphogenetic protein (BMP)-2 and BMP-7 in Boyden chambers, as well as in micro-slide chemotaxis chambers. 13 SDF-1 has previously been shown to recruit more host stem cells to a fracture defect site and to encourage osteogenic differentiation and production of bone. 14 …”