As described earlier in this chapter, bone is a metabolically active organ, undergoing throughout life a continual turnover and remodeling process involving bone resorption followed by accretion. The balance between the rates of bone resorption by osteoclasts and bone formation by osteoblasts will determine, both at a local level or globally (the entire skeleton), whether there is a negative, neutral, or positive calcium balance. The biological activities of bone cells are subject to the actions of a multitude of hormones, cytokines, and other physiological regulators (see Table 1). A summary of the physiological effects of calcitonin, para thyroid hormone, and vitamin D metabolites related to mineral metabolism in presented in Table 2.

Table1. Modulators of Bone Cell Resorptive Activity

Table2. Physiological Effects of Calcitonin, Parathyroid Hormone, and Vitamin D (Metabolites) Related to Mineral Metabolism ^a

Considering that PTH and 1α,25(OH)2D3 both stimulate bone resorption, it is surprising that the bone resorbing cells, the osteoclasts, do not have either a PTH receptor or the 1α,25(OH)2D3 receptor (VDR). The process of osteoclastogenesis is complex (see Figure 1) and is supported by a collaboration between osteoblasts with osteoclast progenitor cells derived from a monocytes/macrophage lineage. The osteoclast progenitor cells are stimulated by macrophage colony stimulating factor (M-CSF) to initiate the production of the cell surface receptor RANK (receptor activator for nuclear factor κB). This is followed by PTH binding to its osteoblast plasma membrane receptor in collaboration with genomic actions of 1α,25(OH)2D3 in the osteoblast to stimulate the production of RANKL, the ligand for the maturing osteoclast’s RANK receptor. Note that the ligand for RANK does not diffuse from one cell to the other. Instead the ligand (RANKL) for the osteoclasts’ RANK is tethered on the extracellular surface of the osteoblast’s plasma membrane. Thus the “message” of the hormone RANKL is basically delivered when the two cells (osteoblast and osteoclast) are in extremely close proximity to one another. The binding of RANKL to its RANK can be inhibited by osteoprotegerin (OPG). Osteoprotegerin (OPG), also known as osteoclastogene sis inhibitory factor (OCIF), is a decoy soluble receptor for RANKL which can inhibit the production of osteo clasts. The net outcome of this overall process is that the osteoclast precursors (prefusion osteoclasts and multi nucleated osteoclasts) are stimulated to fuse and form mature, activated, fully functional osteoclasts.

Fig1. A schematic pathway of osteoclastogenesis supported by osteoblast/stromal cells. Osteoclast progenitor cells are derived from a monocytes/ macrophage lineage. They enter into a differentiation pathway starting with stimulation by M-CSF (monocyte/macrophage colony stimulating factor) that binds to its cell surface receptor, c-Fms. This results in the appearance of the cell surface receptor, RANK (the receptor activator of NF-κB ligand) on several cell types including osteoclast progenitors, prefusion osteoclasts, multinucleated osteoclasts, and fully activated and functional osteoclasts. RANKL, which is present on the cell surface of osteoblasts/stromal cells, is the ligand for RANK. The binding of RANKL to RANK results in communication between the osteoblast (which possesses PTH, IL-11 and 1α,25(OH)2D3 receptors) with the progenitor osteoclasts, prefusion osteoclasts, multinucleated osteoclasts and functional activated osteoclasts. OPG is a decoy soluble receptor for RANKL produced by osteoblasts that acts as a decoy receptor for RANKL and thereby inhibits osteoclastogenesis and osteoclast activation by binding to RANKL. Interleukin-11 (IL-11) is a 23 kDa protein that participates in osteoclast progenitor proliferation and differentiation into prefusion osteoclasts. VDR is the receptor for 1α,25(OH)2D3 that is present in osteoblasts, but not osteoclasts.

The process of bone formation and bone resorption can be mediated by a bone remodeling unit (BRU) which comprises the integrated and sequential actions of first osteoclasts followed by osteoblasts. The detailed functioning of this model through the phases of activation, resorption, reversal, formation, and mineralization is described in Figure 2. A series of sequential steps which constitute the operation of the BRU are initiated. They include the following: (a) osteoclasts accumulate on the surface of bone and begin to carry out bone resorption, which results in creation of a pit or trench; (b) integrated with step (a) is the phagocytosis of the uncovered bone matrix debris; (c) osteoblasts begin to appear at the trench and slowly put in place in the trench osteoid, which is followed by (d) laying down new calcium hydroxyapatite bone mineral so as to completely fill the trench.

Fig2. Schematic illustration of the activities of a bone remodeling unit (BRU). A cluster of osteoclasts have hollowed out in old bone a downward tunnel at a rate of ~50 μm/day. (The biological properties of the working osteoclast cells are summarized in Figure 3.) The osteoclasts are followed by osteoblasts which will lay down a new bone matrix and implement a new importation of calcium and phosphate to create the calcium-hydroxyapatite precipitate which will ultimately close the tunnel by concentric layers of new bone at a rate of 1–3 μm/day (a 3–4 month interval). Some of the osteoblast cells will become trapped in the new bone mineral and will become osteocytes. Associated with the tunneling activity is the generation of a small blood vessel or capillary sprouts that will provide the cells with nutrients and oxygen and remove CO2 as hydrogen carbonate HCO3−.

Depending on physiological and mechanical needs, the osteoclasts create resorption trenches in pockets of existing cortical or trabecular bone (Figure 3). In any given time interval, it has been calculated that the adult human skeleton has more than one million functional trenches or BRU in operation. For any given BRU, the bone resorption removal phase requires several weeks to achieve completion. In healthy bone with active BRU, after the completion of the resorption process, then the lost calcium hydroxyapatite is replaced via a process requiring 3–4 months to fill the BRU.

Fig3. Schematic illustration of the activities of an osteoclast vigorously engaged in bone resorption. The osteoclast basolateral membrane has ATP dependent ion transport systems to extrude calcium (which has been solubilized from the bone’s precipitated calcium hydroxyapaptite). The osteoclast is enriched in mitochondria to provide the large amount of ATP necessary for these pumps as well as for an electrogenic proton pump, which raises the hydrogen ion concentration outside the ruffled border area. Lysosomal enzymes are synthesized and taken up in Golgi vesicles that contain mannose 6-phosphate receptors. These vesicles exocytose across the ruffled border membrane, so as to discharge their enzyme contents outside the osteoclast where Ca2+ resorption and local bone matrix breakdown is actively occurring. The sealing zone, with its actin filaments and specialized attachment structures (podosomes), surrounds the ruffled border area and separates it from the extracellular fluid. Also it is postulated that the bone matrix protein, osteopontin, plays a role in anchoring actively resorbing osteoclasts to the bone. Carbonic acid is generated from the CO2 produced by mitochondrial metabolism and provides the source for hydrogen ions to be pumped across the ruffled border. Any excess HCO3− is removed by exchange with chloride. While receptors for calcitonin are expressed in the plasma membrane, no receptors for either PTH or 1α,25(OH)2D3 are present in the osteoclast even though both hormones contribute to bone resorption.

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مواضيع ذات صلة

Calcitonin Receptor and Biological Actions

Parathyroid Hormone-Related Protein Receptor and Biological Actions

Parathyroid Hormone Receptor and Biological Actions

T3 Inhibition of TSH and TRH Gene Expression

Mechanism of T3 Action

Role of Thyroid Hormone in Thermogenesis

Metabolism of Thyroid Hormone :Deiodination

Thyroid Hormone Transporters

Ghrelin, Leptin, and Energy Use

Coordination of Gastroenteropancreatic Hormone Release

Pancreatic, Biliary, and Intestinal Secretions

Hormone-Secreting Cells: Their Distribution in the Gastroenteropancreatic Complex