Osteoclasts membrane functions

Zaidi M, Shankar VS, Tunwell R, Adebanjo OA, Mackrill. 1. Pazianas M, O Connell D, Simon BJ, Rifkin BR, Venkitaraman AR, Huang, CL-H, Lai FA. 1995. A ryanodine receptor-like molecule expressed in the osteoclast plasma membrane functions in extracellular Ca2+ sensing. J Clin Invest 96 1582-90. 

FIGURE 10.17 Proton pumps cluster on the ruffled border of osteoclast cells and function to pump protons into the space between the cell membrane and the bone surface. High proton concentration in this space dissolves the mineral matrix of the bone. 

CalcitrioPs action primary function is in regulating plasma calcium concentration. In health, the plasma total calcium concentration is tightly controlled at 2.35-2.55 mmol/1. Only the ionized or free fraction, amounting to about 50% of the total, is physiologically active in for example, maintenance of membrane electrical potential and bone formation. The hormone causes increased bone resorption via activation of osteoclasts (see Section 9.4) and increased intestinal absorption of calcium following the synthesis of a specific binding protein in mucosal cells. As described in Section 4.7, some... 

A possible involvement of a unique cell surface-situated RyR by which extracellular [Ca2+] is transduced into changes in intracellularly stored [Ca2+] nevertheless leaves a number of mechanistic questions unresolved. It remains uncertain as to whether the RyR-2 also itself functions as the Ca2+ sensor, conceivably through its intraluminal low-affinity Ca2+ binding site (Anderson et al., 1989) or is coupled to a distinct intramembrane entity of the conventional 7-pass G-protein coupled types described elsewhere (Kameda et al., 1998). The mechanism by which such a surface event would induce a release of intracellularly stored Ca2+ remains unclear. Finally, the role of such a unique surface membrane site in the osteoclast for the RyR in longer term osteoclast regulation certainly merits further exploration (Adebanjo et al., 1999 Gerasimenko et al., 1995 Santella Carafoli, 1997). 

Oursler, M.J., Collin-Osdoby, P., Li, L., Schmitt, E., and Osdoby, P. 1991. Evidence for an immunological and functional relationship between superoxide dismutase and a high molecular weight osteoclast plasma membrane glycoprotein. J. Cell. Biochem. 46, 331-344. 

Despite the substantial amounts of Na+ ions released from demineralized bone and entering the cytosol in exchange for protons, excessive amounts of dihydrogen phosphate (HjPO also enter the cytosol. To compensate, there is a separate inward diffusion of disodium monohydrogen phosphate (NajHPO from the periosteum/bone marrow through Pit-2 transporters (Sect. 9.3.5) in the osteoclast basolateral membrane (Fig. 10.2). Nevertheless, the pH eventually falls below levels compatible with mitochondrial function, perhaps explaining the osteoclast s short half-life. 

When ODAR attaches to the osteoblast surface-bound ODF, the receptor/ligand complex activates a membrane-associated tyrosine-protein kinase to induce synthesis of the ruffled membrane. A tyrosine residue on C1IC-5 (Sect. 10.1.4) is phosphorylated by an activated protein kinase, called c-src, the normal cytosolic homologue of a viral tyrosine kinase which causes a sarcoma (transforms fibroblasts into cancer cells). The phosphorylated C1IC-5 interacts with phospholipids, a chloride channel protein (C1C-7) and two transporter proteins, the ATPase proton transporter, and the proton-dependent phosphate transporter. Mutations that suppress c-src or prevent expression or functioning of C1C-7 or C1IC-5 in mice or humans prevent osteoclast development and cause overly dense, brittle bones (osteopetrosis). 

Ninety percent of cancer deaths are caused by metastatic rather than primary tumors. Define metastasis. Explain the rationale for the following new cancer treatments (a) batima-stat, an inhibitor of matrix metalloproteinases and of the plasminogen activator receptor, (b) antibodies that block the function of integrins, integral membrane proteins that mediate attachment of cells to the basal laminae and extracellular matrices of various tissues, and (c) bisphosphonate, which inhibits the function of bone-digesting osteoclasts. 

Metal ions released from metal implants by osteoclastic bio-corrosion are distributed through- out the body and are eventually taken up by dendritic cells, the most potent anti-gen-presenting cells [14, 15, 18]. Besides changing phenotypic and functional properties of dendritic cells [18], metal ions complex with cellular proteins and peptides. In case of titanium, the ions form complexes with phosphorus-containing proteins and peptides (usually signaling molecules), nucleotides (DNA in the nuclease and RNA in the cytoplasm) and lipids (phospholipids of the cellular membranes) [15]. The new antigenic metal-peptides are presented by dendritic cells to specific T-lymphocytes that react and are activated [15]. The dendritic cells and activated T-lymphocytes accumulate in tissues with high metal concentrations, usually close to the metal implant, and form inflammatory reactions [7] that include secretion of inflammatory cytokines, such as TNF-a, TGF-b, interleukin-6 and interleukin-lb [19]. Most important is secretion of RANK-L by the activated T-lymphocytes, an essential factor for maturation, survival and function of osteoclasts [19]. 

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