Nano-Hydroxyapatite Stimulation of Gene Expression Requires Fgf Receptor, Phosphate Transporter, and Erk1/2 Signaling

Hydroxyapatite (HAp) is critical to health both as the main structural material of the skeleton and storage material of calcium and phosphate. Nanosized HAp (nHAp) is naturally produced by mineralizing cells during bone formation and remodeling and is the main constituent of the skeleton. As such, HAp is currently being investigated as a therapeutic biomaterial for orthopedic and dental purposes. Recent studies have suggested that extracellular nHAp can influence osteoblast lineage commitment and cell function through changes in gene expression; however, the mechanisms remain to be elucidated. Here, the cellular and molecular mechanism by which rod shaped nHAp (10 X 100 nm) stimulates gene expression in preosteoblast bone marrow stromal cells was investigated. Electron microscopy detected a rapid and stable interaction of nHAp with the cell membrane, which correlated with a strong stimulation of the Erk1/2 signaling pathway. Results also identified the requirement of the Fgf receptor signaling and phosphate-transporters for nHAp regulated gene expression whereas a calcium sensing receptor inhibitor had no effect. Collectively, the study uncovers novel signaling pathways and cellular events specifically stimulated by and required for the cellular response to free extracellular HAp. The results provide insight into the osteoblastic response to HAp relevant to functional mineralization and pathological calcification and could be used in the development of biomaterials for orthopedic purposes.