ASARM Mineralization Hypothesis: A Bridge Too Far?

Bone is a dynamic load-bearing organ whose structural integrity is maintained by a remodeling cycle that consists of osteoclast-mediated resorption followed by osteoblastmediated deposition of an unmineralized collagen matrix (osteoid). After a delay of several days (as measured by the histomorphometric parameter of mineralization lag time), osteoid undergoes mineralization, which is a complex regulated process. Mineralization of osteoid occurs as a consequence of a balance between inorganic factors, such as the local concentrations of phosphate and pyrophosphates, that respectively promote and inhibit hydroxyapatite formation, as well as extracellular matrix proteins that either facilitate or impede the mineralization process. During the mineralization process, a subset of the osteoblasts becomes embedded in the matrix, forming osteocytes that have dendrite-like cytoplasmic extensions creating a canalicular (neural-like) network inside the mineralized matrix, where they act as both sensors and effectors of skeletal homeostasis. This complex regulation of bone turnover and mineralization allows bone to participate in systemic mineral metabolism. In this regard, bone is a mineral reservoir where calcium and phosphate are in equilibrium with the systemic milieu under steady state, and the influx and efflux of calcium and phosphate from bone are under control of both passive physicochemical forces and active cellular processes, such as systemic hormones and mechanical/local factors. A new concept that has emerged is that bone is also an endocrine organ that releases from osteoblasts and osteocytes fibroblast growth factor 23 (FGF23), a novel hormone that targets the kidney to inhibit renal phosphate reabsorption and 1,25dihydroxyvitamin D [1,25(OH)2D] production. (1–4) One physiologic function of FGF23 is to act as a counterregulatory hormone to 1,25(OH)2D. (1) The other physiologic function of FGF23 appears to be to serve as the ‘‘primary’’ phosphaturic hormone in a bonekidney axis that coordinates renal phosphate handling with bone mineralization and possibly bone remodeling activity. There is a major gap, however, in our knowledge of the molecular mechanisms whereby the mineralization process and FGF23 expression are regulated by osteoblasts and osteocytes.