## 3 Bone Remodeling  
Bone remodeling is a lifelong process that allows the repair of micro damage and the substitution of old or damaged bone with new bone. During physiological bone remodeling, the activity of bone-forming OBs and bone-resorbing OCLs are coupled and strictly controlled in order to maintain bone homeostasis [1]. Indeed, the amount of resorbed bone is totally replaced by new bone in terms of location and amount [1]. Generally, it is customary to distinguish between targeted and non-targeted remodeling. Non-targeted bone remodeling refers to the regulation by hormones (e.g., parathyroid hormone (PTH), estrogens, growth factors), while targeted bone remodeling is responsible for the removal of damaged bone by targeted resorption [8]. As widely described by others, bone remodeling takes place within the basic multicellular unit (BMU), an organized structured consisting of OBs, OCLs, and osteocytes, which allows the formation and resorption activities to occur in a balanced and coupled manner [9; 10; 11]. OBs derive from mesenchymal stromal cells (MSC) and are responsible for bone matrix synthesis and mineralization. OCLs derive from mononuclear progenitors of the monocyte lineage that fuse to form giant multinucleated cells. Osteocytes are terminally differentiated cells of the OB lineage, embedded in the bone matrix within the lacuno-canalicular system. Osteocytes are mechano-sensors and capable of sensing mechanical stimuli and convert these signals into a cellular response to control bone resorption and formation [12; 13]. Lastly, bone lining cells belong to the OB lineage that migrate over the remodeling area, in particular near OCLs, preventing the inappropriate interactions of OCL precursors with the bone surface. The remodeling phase consists of four overlapping steps named activation, resorption, reversal, and formation. The resorption step comprises the early migration of mononuclear OCL precursors from marrow capillary to the bone surface. When differentiated OCLs complete bone resorption, specialized cells remove the undigested product of bone resorption, preparing the bone surface for the subsequent bone formation and providing signals for OB migration (reversal step). In the formation step, OBs begin to deposit unmineralized bone matrix until the resorbed bone is completely rebuilt. When this step is complete, the bone surface is covered by lining cells [1; 14]. In humans, the length of bone remodeling is approximately 4-6 months. The resorption step is preceded by the activation step in which different signals, such as mechanical and nutritional stress as well as hormones (e.g., PTH, estrogen), provide the key message to ensure a proper OCL recruitment [1]. Osteocytes play a pivotal role in this phase. In particular, during targeted bone remodeling, dying or dead osteocytes (e.g., induced by structural damage of bone matrix) induce the secretion of RANKL by OBs. In addition, osteocytes can themselves produce RANKL, thus contributing to the recruitment of OCL precursors [13]. The beginning of the resorption step is mediated by cells of OB lineage, osteocytes, lining cells, and preOBs, which respond to signals described above. For example, in response to PTH stimulation, OBs produce monocyte chemoattractant protein-1 (MCP-1), a chemoattractant chemokine for OCLs [15]. Moreover, OBs secrete RANKL and macrophage colony-stimulating factor (M-CSF). The interaction of RANKL with the receptor RANK expressed by OCL precursors results in the activation and differentiation of OCL precursors. M-CSF interacts with its receptor c-Fms expressed by OCL precursors promoting their proliferation and survival as well as motility and cytoskeletal organization in mature OCLs [16]. Osteoproteger (OPG) is a glycoprotein belonging to the tumor necrosis factor (TNF) receptor family secreted by cells of the OB lineage that acts as a soluble decoy receptor for RANKL [17]. OPG inhibits the activation and differentiation of OCLs and induces their apoptosis.