Calcium and bone disease

Abstract

Calcium transport and calcium signaling are of basic importance in bone cells. Bone is the major store of calcium and a key regulatory organ for calcium homeostasis. Bone, in major part, responds to calcium-dependent signals from the parathyroids and via vitamin D metabolites, although bone retains direct response to extracellular calcium if parathyroid regulation is lost. Improved understanding of calcium transporters and calcium-regulated cellular processes has resulted from analysis of genetic defects, including several defects with low or high bone mass. Osteoblasts deposit calcium by mechanisms including phosphate and calcium transport with alkalinization to absorb acid created by mineral deposition; cartilage calcium mineralization occurs by passive diffusion and phosphate production. Calcium mobilization by osteoclasts is mediated by acid secretion. Both bone forming and bone resorbing cells use calcium signals as regulators of differentiation and activity. This has been studied in more detail in osteoclasts, where both osteoclast differentiation and motility are regulated by calcium.

Fig. 1

The osteon and vectorial transport of mineral. The bone forming unit, or osteon, is comprised of surface cells (osteoblasts) and cells buried in matrix (osteocytes), all connected by gap junctions and separated from the extracellular fluid by tight junctions. Bone mineral is accumulated by active formation of phosphate and passive calcium transport, with an alkaline pH maintained to allow the mineral to precipitate despite the evolution of H¹, which is required by the stoichiometry (see text). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Fig. 2

Transport processes in the osteoclast that mediate calcium mobilization. The osteoclast is a multinucleated cell that attaches to mineralized tissues by close association of cell membrane using an alphav beta3 integrin ring. Within the compartment thus produced, the cell expresses a specialized organelle, the ruffled border, in which large quantities of vacuolar-(V) type H1-ATPase are inserted. A special membrane component of the V-ATPase is essential for this distribution. In addition, at least two further transporters, a chloride channel and a chloride proton exchanger, occur and dissipate the voltage gradient produced by the V-ATPase, which is electrogenic (that is, transports H1 without a balancing ion). Cellular pH is maintained by bicarbonate transporters at the basolateral surfaces of the cell. Calcium liberated by acidification is moved through the cell by vacuolar transcytosis [57,58]. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]