[Truncated abstract] Bone is a living tissue that is undergoes a continuous process of remodeling during and after skeletal development. The process is to change the shape of the bone to accommodate the growth of the individual as well as to maintain bone integrity throughout life. It also plays a role in the regulation of calcium homeostasis, as bone is mainly composed of calcium minerals and thus a major reservoir for calcium. Two resident bone cell types are primarily responsible for bone remodeling: 1) osteoblasts and 2) osteoclasts. Osteoblasts are essentially bone-forming cells, whereas osteoclasts function to resorb bone surfaces. A balance between the activity of bone formation and bone resorption must be maintained in order to sustain bone structure stability. An imbalance in the activity of bone formation and bone resorption has been the underlying cause of many bone diseases such as osteoporosis and Paget’s disease of the bone. Osteoclasts are large multinucleated cells that are formed by the fusion of mononuclear progenitors of the monocyte-macrophage family. These cells attach themselves to the bone surface and form a sealed compartment, known as the resorption lacuna, between the cell membrane and the bone. H+ ions and osteolytic enzymes are pumped into the resorption lacuna from the osteoclasts to degrade the bone’s mineral and organic matrix. Stromal cells and osteoblasts are essential for osteoclast formation (osteoclastogenesis) as they produce the two essential molecules that are involved in the process: 1) macrophage colony-stimulating factor (M-CSF) and 2) receptor for activation of nuclear factor kappa B (NFκB) (RANK) ligand (RANKL). RANKL alone is sufficient to induce a murine-derived macrophage cell line (RAW264.7) to form bone-resorbing osteoclasts. RANKL is a transmembrane protein found on stromal cells or osteoblasts that binds to RANK. RANK is a transmembrane protein expressed on the cell surface of osteoclasts. The binding of RANKL to RANK stimulates it, inducing osteoclastogenesis, osteoclastic bone resorption, and osteoclast survival. Protein Kinase C (PKC) is a family of threonine/serine kinases, which consists of several different isoforms. These isoforms are grouped into three groups: 1) classical PKCs (cPKCs), 2) novel PKCs (nPKCs), and 3) atypical PKCs (aPKCs). These groups are formed on the basis of their different activation requirements. cPKCs are calcium-dependent and activated by both phosphotidylserine (PS) and diacylglycerol (DAG). vii nPKCs are calcium-independent, but are still regulated by PS and DAG. aPKCs are calcium independent and do not require DAG for activation, although PS can regulate their activity. PKCs play a crucial role in signal transduction for a variety of biologically active substances that activate cellular functions and proliferation...
|Publication status||Unpublished - 2009|