Downregulation of SOST/sclerostin by PTH: a novel mechanism of hormonal control of bone formation mediated by osteocytes.

Both chronic excess of PTH, as in hyperparathyroidism, and intermittent elevation of PTH (by daily injections) increase the number of osteoblasts. However, whereas the former condition can lead to bone catabolism, intermittent administration of PTH causes bone anabolism. The striking difference between bone loss and bone gain in the two conditions might result from a negative vs. positive balance between formation and resorption within each bone remodeling unit, or from de novo bone formation not coupled to previous resorption in the case of intermittent PTH administration. In any event, increased osteoblast number can be achieved by increased osteoblast production from progenitors, or decreased osteoblast apoptosis, or a combination of the two events. Studies in mice indicate that chronic and intermittent PTH increase osteoblast number by distinct mechanisms (Figure 1). Thus, whereas the increase in osteoblast number and the anabolic effect of intermittent PTH in cancellous bone can be accounted for by attenuation of osteoblast apoptosis, chronic elevation of endogenous PTH had no effect on osteoblast survival. The osteoblast specific transcription factor Runx2 is required for the antiapoptotic effect of PTH; however, PTH also stimulates proteasomal proteolysis of Runx2. Based on this, we have reasoned that repeated injections of the hormone are needed to inhibit osteoblast apoptosis because the duration of the PTH-induced survival signaling is self-limited by downregulation of Runx2; and that the inability of chronic elevation of PTH to attenuate osteoblast apoptosis may be due to a decrease in Runx2 levels below the threshold needed for survival signaling. Nevertheless, the increase in osteoblasts seen with chronic PTH elevation cannot be accounted for by inhibition of osteoblast apoptosis and therefore must result from increased osteoblast production. Recent studies indicate that the osteoblastogenic action of chronic elevation of PTH may result from actions of the hormone on osteocytes via changes in Sost expression. Consistent with evidence that Sost is upregulated by Runx2 and that PTH induces proteasomal degradation of Runx2 protein, continuous elevation of PTH dramatically reduces the expression of Sost mRNA and sclerostin in osteocytes in vivo and in vitro. These findings demonstrate a direct effect of PTH on osteocytes and were independently confirmed by other investigators. PTH also acts on stromal/osteoblastic cells to stimulate the production of growth factors and J Musculoskelet Neuronal Interact 2006; 6(4):358-359