# Nanomaterials in Bone Regeneration
## 2 Bone Biology
### Bone Cells  
The major types of bone cells are osteoblasts, osteoclasts, osteocytes, and bone lining cells. All four types of bone cells are involved in growth, repair, regulation, and all other functions of skeletal tissues (Figure 2). The term \"osteoblast\", as a combination of the Greek (bone) and (germinate), was first used in the early 20 th century as a cell from which literally \"germinate bone\" [37]. Morphologically, it is a cubic to cylindrical cell with a strongly basic cytoplasm located at the interface of newly synthesized bone. Osteoblasts are present in bone throughout life, but their activity is highest during embryonic skeletal development and growth. In the adult organism, osteoblasts are activated when there is a need to regenerate damaged bones or to form bone matrix [38]. Osteoblasts produce bone matrix proteins such as type I collagen (Col1), osteoclast (OC), or alkaline phosphatase (ALP). Osteoblasts are post-mitotic cells but are not finally differentiated. Osteoblasts gradually surround the bone matrix and can differentiate into osteocytes, which are interconnected stellate cells. Osteoblasts that remain on the outer layer toward the periosteum can either turn into bone lining cells or undergo apoptosis. If the amount of osteoblasts decreases, either as a result of natural turnover or during an excessive regenerative process, new cells are differentiated  
Figure 2: The microscopic structure of the bone and types of bone cells. The cells are not of comparable size. from mesenchymal progenitor cells [39]. Osteoblasts are able to form osteoids (collagen I rich matrix), which are subsequently calcified. The corresponding impulse directs the active osteoblast characterized by a large number of endoplasmic reticulum as well as a large number of Golgi complexes from its mesenchymal progenitor cell located in the bone marrow. Osteoclasts are multinucleated cells responsible for bone matrix resorption. They are derived from hematopoietic stem cells, specifically from the macrophage lineage. Through their activity, they dissolve bone minerals and create an optimal environment for enzymes involved in the degradation of the demineralized extracellular bone matrix. As osteoblast antagonists, they maintain homeostasis between bone formation and resorption. This complex activity is primarily controlled by the nuclear factor \(\kappa\beta\) receptor activator (RANK) and its ligand (RANKL). Under the anabolic processes or under the influence of osteoer-sorption factors such as glucocorticoids, calcitriol, or parathyroid hormone, osteoblasts release RANKL, which binds to the RANK receptor on proosteoclast cells and turns them into fully functional osteoclasts [40]. The mature osteoclast is a functionally polarized cell adjacent to the mineralized bone matrix by its apical pole. This connection is formed by a specific interaction between an adhesion molecule integrated into the cell membrane (integrin) and specific bone matrix proteins. The apical part of the osteoclast is invaginated, creating a free space between its roughly wrinkled membrane and the adjacent bone, into which it actively draws the substances needed for resorption [41]. One of the main tasks of the osteoclast is to acidify the resulting resorption space. The cell is richly equipped with the enzyme carbonic anhydrase, which catalyzes the reaction of water and carbon dioxide to form a proton (H\({}^{+}\)) and bicarbonate (HCO\({}_{3}\)\({}^{-}\)) anion. The protons are then actively pumped by a proton pump into the resorption space [42]. The regulation of this transport, which is closely linked to the regulation of intracellular pH and membrane potential, is maintained by ion pumps and channels on the basolateral side of the cell. The activity of the mature osteoclast is negatively regulated by calcitonin (CT), for which a large number of receptors are expressed [43].