Building bone with a SOST-PTH partnership

Abstract

T he discovery of the SOST gene, whose protein product, sclerostin, is an osteocyte-derived inhibitor of Wnt signalling and bone formation, (1,2) has provided a major advance in bone biology. It gives us new insights into the communicating networks among bone cells and, importantly, to new ways of restoring bone once it has been lost. In the current issue of JBMR, Kramer and colleagues complement their earlier demonstration that parathyroid hormone (PTH) inhibits sclerostin expression (3) to show that the anabolic effect of PTH is blunted both in mice overexpressing sclerostin and in SOST null mice. (4) PTH administered by daily injection is the only currently available anabolic therapy for bone. (5,6) While a number of contributing pathways, including direct prodifferentiation (7) and antiapoptotic (8) actions on osteoblasts, as well as couplingrelated activity through the osteoclast, (9) have been proposed, the full mechanism of action of anabolic PTH remains obscure. Another contributory mechanism was introduced by the discovery of sclerostin and its regulation by both PTH and PTH-related protein (PTHrP) via a distal enhancer of the SOST gene. (3,10) The experiments reported by Kramer and colleagues (4) provide further evidence that sclerostin regulation may play a part in PTH anabolic action. Mice overexpressing sclerostin have less bone as a result of decreased bone-formation rate, as described previously. (11) When these mice were treated with a high dose of PTH, sufficient to increase trabecular bone volume (BV/TV) in wild-type mice, no increase in trabecular bone volume was detected despite a robust reduction in sclerostin expression. It is worth noting that even though sclerostin mRNA levels are reduced by PTH in the transgenic model, total sclerostin expression after PTH treatment is still greater than in wild-type mice. This high level of sclerostin expression, the basal phenotype of a mild reduction in bone remodeling, or both impair the effect of PTH on BV/TV. Surprisingly, even though BV/ TV was not increased, all histomorphometric markers of bone formation, as well as the osteoclast surface, were substantially elevated by PTH treatment in the sclerostin transgenic mice to approximately the same extent as that observed in wild-type mice. Thus a question in the sclerostin transgenic model remains as to how PTH can increase bone turnover without altering BV/ TV. Is osteoclast function enhanced? No evidence was obtained for that. An alternative explanation could be that the sclerostin overexpressing mice lay down bone of reduced quality that is easier for osteoclasts to resorb. The quality of bone in the sclerostin overexpressing mouse is not yet known. Resolving this paradox may provide useful information about the interaction between osteoclasts and osteoblasts in the presence of high levels of sclerostin and, presumably, low levels of b-cateninactivated gene transcription.In SOST null mice, as expected from the skeletal abnormalities observed in van Buchem disease and sclerosteosis, (12) trabecular...

Aging periosteal progenitor cells have reduced regenerative responsiveness to bone injury and to the anabolic actions of PTH 1-34 treatment

“…In normal bone, PTH induces β-catenin signaling through 1) direct activation of the signaling pathway by association with the LRP5/6 or disheveled receptors; 2) induction of Wnt protein expression; or 3) down-regulation of Sost expression in osteocytes [31, 33, 62-65]. A role for β-catenin in fracture healing is clearly established in studies demonstrating that antibody blockade of SOST and DKK1 result in accelerated fracture healing [66-68].…”

Osteoimmunology: oncostatin M as a pleiotropic regulator of bone formation and resorption in health and disease

“…OSM action via two different receptor complexes that activate JAK-STAT signaling (OSMR/gp130 and LIFR/gp130) give different cellular outcomes via different target cells, affecting osteoblast/stromal cell RANKL and osteocyte sclerostin, respectively, in vivo and in vitro. 25 Its actions on bone have a number of parallels with those of PTH, which also exerts its actions via several different cellular targets, 69 including OSMR and gp130. This suggests that the careful dissection of intracellular pathways elicited by OSM (and related cytokines) and evaluating the roles of its target cells in bone could lead to important insights into the design of novel anabolic therapies for bone.…”

The immune system and bone

“…The relevance of sclerostin in the mechanism of action of PTH remains uncertain because studies with sclerostin transgenics and sclerostin KO mice have not provided conclusive evidence that this osteocytic peptide is the key target of PTH (113,114). …”