Metal Ions Induce Myofibroblastic Differentiation of Mesenchymal Stem Cells

Despite recent advances in the biomaterials field, metal implant corrosion remains a pertinent clinical issue. Implanted metals, including stainless steel, titanium and titanium alloy are subject to wear and corrosion. This process releases metal ions, which stimulate fibrous tissue formation, and lead to impairment of osseointegration and implant failure. Metal ions impair osteogenesis, however, the molecular mechanisms by which metal ions direct tissue differentiation have yet to be identified. Transforming growth factor beta (TGF-β) drives fibrotic responses, impedes osteoblast differentiation and induces myofibroblast differentiation. TGF-β must be activated to induce fibrogenesis. Activation of latent TGF-β occurs by multiple mechanisms, including oxidative modification of the latent complex and binding to thrombospondin-1 (TSP1). Bone marrow-derived mesenchymal stem cells (MSCs) are pluripotent, home to sites of tissue injury, and play a role in both normal and fibrotic repair responses. Mesenchymal stem cells can differentiate into myofibroblasts, which have been implicated in fibrous tissue formation surrounding metal implants.

Objective: These studies tested the hypothesis that TSP1-dependent TGF-β activation is important for fibrotic responses to titanium, titanium alloy and stainless steel ions.

Methods: Metal ions were used to mimic the composition of titanium, titanium alloy and stainless steel ions in vitro. The ability of these metal ions to regulate levels of TGF-β activity and myofibroblastic differentiation of human MSCs was evaluated in vitro by the PAI-1 luciferase reporter assay, immunofluorescence, and immunoblot analyses. TSP1 and p-Smad expression levels were looked at in tissue sections from retrieved implants.

Results: Metal ion treated MSCs showed increased levels of TGF-β activity and expression of myofibroblast markers, partially due to TSP1-dependent TGF-β activation. Furthermore, treatment with metal ions impaired osteogenesis. Human implant tissue section showed increased levels of TSP1 and TGF-β.

Conclusion: TSP-dependent TGF-β activation may play a role in fibrous tissue formation surrounding metal implants.

F30 DE018259-01A1