Abstract
BackgroundBisphosphonates are therapeutics of bone diseases, such as Paget's disease, multiple myeloma or osteoclastic metastases. As a severe side effect the bisphosphonate induced osteonecrosis of the jaw (BONJ) often requires surgical treatment and is accompanied with a disturbed wound healing.Therefore, the influence on adhesion and migration of human osteoblasts (hOB) after bisphosphonate therapy has been investigated by morphologic as well as gene expression methods.MethodsBy a scratch wound experiment, which measures the reduction of defined cell layer gap, the morphology and migration ability of hOB was evaluated. A test group of hOB, which was stimulated by zoledronate 5 × 10-5M, and a control group of unstimulated hOB were applied. Furthermore the gene expression of integrin aVb3 and tenascin C was quantified by Real-Time rtPCR at 5data points over an experimental period of 14 days. The bisphosphonates zoledronate, ibandronate and clodronate have been compared with an unstimulated hOB control.ResultsAfter initially identical migration and adhesion characteristics, zoledronate inhibited hOB migration after 50 h of stimulation. The integrinavb3 and tenascin C gene expression was effected by bisphosphonates in a cell line dependent manner with decreased, respectively inconsistent gene expression levels over time. The non-nitrogen containing bisphosphonates clodronate led to decreased gene expression levels.ConclusionBisphosphonates seem to inhibit hOB adhesion and migration. The integrin aVb3 and tenascin C gene expression seem to be dependent on the cell line. BONJ could be enhanced by an inhibition of osteoblast adhesion and migration. The gene expression results, however, suggest a cell line dependent effect of bisphosphonates, which could explain the interindividual differences of BONJ incidences.
Highlights
Bisphosphonates are therapeutics of bone diseases, such as Paget’s disease, multiple myeloma or osteoclastic metastases
Since adhesion and migration are important factors of wound healing, this study aimed to investigate the influence of zoledronate on osteoblast by morphologic cell culture experiments as well as integrin aVb3 and tenascin C gene expression
Cell migration tests - Scratch Wound Human osteoblasts (HOB-c, Promo Cell, Heidelberg, Germany) between passages 5-7 were cultured on 6-well plates, covering the whole bottom of the well after five days of cultivation
Summary
Bisphosphonates are therapeutics of bone diseases, such as Paget’s disease, multiple myeloma or osteoclastic metastases. Bisphosphonates are proven to be effective in the treatment of benign or malignant skeletal diseases characterized by enhanced bone resorption. They are comprised of two phosphate groups, which are capable of binding divalent ions, such as Mg2+ and Ca2+. Osteoblast migration is regulated by several surface proteins, such as integrins These are responsible for cell adhesion as well as cell signaling [4,5]. Tenascin as well influences cell shape and inhibits the activity of the focal adhesion kinase, an intracellular protein binding the integrins and accumulating vinculin, talin and a-actinin in the focal adhesion site [6,7,8]. Tenascin C knockout mice showing an altered fracture healing, it seems to be an important regulator of osteoblast migration during wound healing [12]
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