ReviewIntegrins as linker proteins between osteoblasts and bone replacing materials. A critical review
Introduction
Bone is a dense, specialized form of tissue, containing three types of cells, i.e. osteoblasts, osteocytes, and osteoclasts. Osteoblasts deposit new bone matrix, osteocytes are the matured osteoblasts that have become entrapped in the deposited bone matrix, and osteoclasts are the cells that break down the bone matrix. For cell culture purposes, osteoblasts can be derived from complete bone. Also, mesenchymal stem cells isolated from the bone marrow can differentiate into osteoblasts, when the right stimuli are provided. As a basic model to analyze cell behavior, frequently cell lines are used, isolated from osteosarcomas [1], [2]. The advantage is that these cell lines show a limited variability, in contrast to untransformed osteoblasts. A big disadvantage of cancerous cells however, is that they have lost many of their osteogenic features.
Acquired or inherited bone defects can be regenerated with the help of a wide variety of materials. Autografts, allografts, and xenografts all have their specific disadvantages, like a second site of surgery, limited availability, transfer of disease, immunological danger, and viral contamination [3], [4], [5], [6]. Also synthetic materials can be applied as bone grafts, with proven usefulness [6], [7].
Implants manufactured of titanium or one of its alloys are used for the replacement of lost teeth and deteriorated hip and knee joints. Titanium interacts with biologic fluids through an oxide layer, which gives titanium its biocompatibility [8], [9], [10], [11]. The oxide layer is formed when titanium is in contact with air, and this layer gives resistance to corrosion. Such titanium implants can be provided with a calcium phosphate (CaP) coating. This coating can have many different compositions and topographies, depending upon the chemical composition of the parent material and the technique used to apply the coating. These CaP coatings resemble the mineral phase in normal bone. The benefits of these CaP coatings are well tested in vivo and in vitro. CaP is bioactive and increases implant fixation due to a chemical bonding with the surrounding bone [8], [9], [10], [12], [13], [14].
When an implant material is placed in a tissue defect, or in culture medium (in vitro), proteins will adsorb to the surface of the implant material. This protein layer will subsequently mediate the interaction of the implant material with the cells arriving from the surrounding tissue. The adhesion molecules involved in this process of cellular adhesion are the integrins, which can also pass information from the extracellular matrix (ECM) to the cell, and from the cell to the ECM. These signaling pathways can regulate cell behavior to a certain extent. Many different materials are used in biomaterial research, and the materials all elicit a different tissue response. It is supposed that integrin expression plays a role in the cellular behavior. In the present critical review, we will focus on research that has been performed with bone replacing materials, integrin expression, and cell behavior.
Section snippets
Cell adhesion and integrins
Cell adhesion can be divided into two phases: the attachment phase and the adhesion phase. Cellular attachment takes place rapidly with short-term events, like physicochemical linkages between the cell and the material. The adhesion phase occurs in the longer term, involving three types of proteins: ECM proteins, cell membrane proteins, and cytoskeletal proteins [15]. The primary family of cell membrane proteins that mediate the adhesion of cells to substrates, are the integrins.
Implants and osteoblasts
When an implant is placed in a defect or in culture medium, the physiological environment will immediately condition the surface with biological fluid components. The surface will be coated with either blood components, or proteins from the serum that is added to the culture medium. Therefore, in vivo and in vitro, cells will never “see” the original surface, but encounter a protein-coated surface layer [15].
After the conditioning of the surface with proteins, cells that express integrins on
Coating of substrates
In some studies, substrates have been coated with ECM proteins, in order to determine their influence on integrin expression, and thus cell adhesion, proliferation, and differentiation. Whether the substrate was composed of glass, titanium, titanium alloy, or polystyrene, coating of the substrate with fibronectin always increased the adhesion, spreading, proliferation, and differentiation of osteoblasts. The formation of focal contacts was also increased on fibronectin-coated substrates [18],
Critical considerations
As can be concluded from the above, many results on cell spreading, focal contacts, and integrins on various chemical compositions and topographies are inconsistent and disagree. Still, some remarks have to be made regarding these studies. It is very important to realize that protein adsorption as well as integrin expression are very dynamic processes. The proteins that have adsorbed to the substrate surface do not become permanently immobilized on the surface. These proteins will be
Conclusion
Until now, most research has been done to investigate the integrin expression of osteoblasts in culture during cellular adhesion. However, a great variety in the culturing systems used makes it impossible to draw generalized conclusions from this research. Nevertheless, we can state that the substrates used and protein or peptide coatings can influence the integrin expression and cell behavior. Additional research has to be done to fully understand all the parameters concerning integrin
Acknowledgements
This research was supported by the Dutch Technology Foundation STW, Grant # NKG.5546, # NGN66.4187, and # NKG.5378.
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