Abstract
Several inflammatory processes underlie excessive bone formation, including chronic inflammation of the spine, acute infections, or periarticular ossifications after trauma. This suggests that local factors in these conditions have osteogenic properties. Mesenchymal stem cells (MSCs) and their differentiated progeny contribute to bone healing by synthesizing extracellular matrix and inducing mineralization. Due to the variation in experimental designs used in vitro, there is controversy about the osteogenic potential of proinflammatory factors on MSCs. Our goal was to determine the specific conditions allowing the pro-osteogenic effects of distinct inflammatory stimuli. Human bone marrow MSCs were exposed to tumor necrosis factor alpha (TNF-α) and lipopolysaccharide (LPS). Cells were cultured in growth medium or osteogenic differentiation medium. Alternatively, bone morphogenetic protein 2 (BMP-2) was used as osteogenic supplement to simulate the conditions in vivo. Alkaline phosphatase activity and calcium deposition were indicators of osteogenicity. To elucidate lineage commitment-dependent effects, MSCs were pre-differentiated prior treatment. Our results show that TNF-α and LPS do not affect the expression of osteogenic markers by MSCs in the absence of an osteogenic supplement. In osteogenic differentiation medium or together with BMP-2 however, these mediators highly stimulated their alkaline phosphatase activity and subsequent matrix mineralization. In pre-osteoblasts, matrix mineralization was significantly increased by these mediators, but irrespective of the culture conditions. Our study shows that inflammatory factors potently enhance the osteogenic capacity of MSCs. These properties may be harnessed in bone regenerative strategies. Importantly, the commitment of MSCs to the osteogenic lineage greatly enhances their responsiveness to inflammatory signals.
Highlights
The autologous bone graft is currently considered the gold standard for bone repair and regeneration, but is associated with disadvantages such as limited availability and donor-site morbidity
To examine the mechanism by which these stimuli are involved in lineage determination, we made a distinction between osteogenic differentiation medium (ODM) or osteogenic medium supplemented with BMP2
We found that short TNF-α or LPS treatment significantly increased the alkaline phosphatase (ALP) activity in differentiating cells, but only if co-delivered with bone morphogenetic protein 2 (BMP-2) or ODM from the start of culture
Summary
The autologous bone graft is currently considered the gold standard for bone repair and regeneration, but is associated with disadvantages such as limited availability and donor-site morbidity. As a bone replacement therapy, osteoconductive materials lack the osteogenic and osteoinductive properties of autografts. They are often combined with mesenchymal stem cells (MSCs) in an experimental setting [2,3]. Bone stimulating factors such as the bone morphogenetic proteins (BMPs) are effective in enhancing bone regeneration, but it is uncertain if the delivery of BMPs alone induces the optimal pro-osteogenic environment required for bone regeneration [4,5]. To better mimic the physiological environment, a new approach is to identify the critical proosteogenic factors involved in inflammation and to harness them to promote bone formation in bone replacement strategies [6]
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