Mechanotransduction in Bone: Dependency on Human Osteoblast Differentiation

Bone is a surprisingly versatile tissue. It provides body shape, protection of vital organs, and enables locomotion. Additionally, it forms a reservoir for calcium, phosphate and bone marrow cells, and is the endocrine organ involved in phosphate homeostasis. It is also a dynamic tissue, while it has the capacity to regenerate, and to change in shape, mass, and quality. Bone is remodeled at such a high speed that approximately 5-10% of the total bone content is replaced per year in adult humans1. Furthermore, bone is a mechanosensitive tissue. Mechanical loading plays a crucial role in maintenance of bone: disuse or unloading may cause osteoporosis, which results in increased fracture risk. Both socially and economically, osteoporosis and its complications have a severe impact on the individual and society. One way to prevent osteoporosis is physical activity. Moreover, physical stimuli have proven to be beneficial in fracture healing and remodeling of malunions. Prerequisite for the maintenance of skeletal homeostasis are cells that degrade old bone (osteoclasts), and those that deposit new bone in its place (osteoblasts). In order to respond to mechanical stress, the physical stimulus needs to be converted into a biochemical signal, eventually resulting in a biological response. This process is called mechanotransduction. Osteoblasts and osteocytes are the main effectors to facilitate this process, equipped with mechanoreceptors on the cell membrane, signal transduction pathways in the cytoplasm, and dedicated ‘mechanosensitive’ genes in the nucleus. Although this concept is generally accepted, little is known on the exact molecular mechanisms that play a role in mechanotransduction in bone. While osteoblasts and osteocytes are both part of the same differentiating lineage, these cells have entirely different characteristics. This thesis focuses on the effects of mechanical loading and human osteoblast differentiation in vitro. This first chapter will provide background information and the rationale for this work.

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