Building bone with a SOST-PTH partnership
Version of Record online: 1 FEB 2010
Copyright © 2010 American Society for Bone and Mineral Research
Journal of Bone and Mineral Research
Volume 25, Issue 2, pages 175–177, February 2010
How to Cite
Sims, N. A. (2010), Building bone with a SOST-PTH partnership. J Bone Miner Res, 25: 175–177. doi: 10.1002/jbmr.53
- Issue online: 19 FEB 2010
- Version of Record online: 1 FEB 2010
The 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 expression3 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 prodifferentiation7 and antiapoptotic8 actions on osteoblasts, as well as coupling-related 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 colleagues4 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 β-catenin-activated gene transcription.
In SOST null mice, as expected from the skeletal abnormalities observed in van Buchem disease and sclerosteosis,12 trabecular bone volume was more than double that of wild-type mice. For this reason, the effects of PTH were studied in young (6- to 8-week old) mice. Even though an early age was chosen, trabecular bone volume and trabecular thickness in particular are already very high in the SOST null mice due to the lack of suppression of mineralization by sclerostin. No significant increase in BV/TV or trabecular bone mineral density (BMD) with even the high dose of 100 µg/kg per day of PTH after 9 weeks of treatment was detected in wild-type (C57Bl/6) mice of this age. This is an issue of some concern, particularly because others have shown dramatic effects of PTH on both these parameters in wild-type mice of C57Bl/6,13, 14 DBA/1,15 mixed strain,16 or unspecified strain17, 18 of this age or younger. It should be noted that in these other studies it is only the treatment regimen of Terauchi and colleagues14 that is directly comparable. The difference in response to PTH between the work of Kramer and colleagues and Terauchi and colleagues is particularly perplexing. Since the effect of PTH in growing long bones is most dramatic near the growth plate, it is possible that the difference between these studies reflects a difference in regions measured; this detail was not reported by Kramer and colleagues, so a direct comparison is not possible.
The treatment and measurement protocols used by Kramer and colleagues did detect a significant increase in trabecular thickness and mineral apposition rate after PTH treatment. This suggests that the dose of PTH used was sufficient to stimulate bone formation, albeit to a lesser extent than that observed by others. This effect was observed in both wild-type and SOST null mice and suggests that the anabolic pathways of PTH and SOST share some common pathways but are not completely overlapping. Trabecular bone formation rate was not increased to the same extent in SOST null mice as observed in wild-type mice treated with PTH, but it must be remembered that bone-formation rate is calculated from both mineral apposition rate and mineralizing surfaces. The latter may have already reached a biologic maximum in the SOST null mice, where more than 60% of trabecular bone surfaces are active bone-forming surfaces. It is difficult to determine whether the influence of PTH on bone-formation rate is reduced because of the absence of sclerostin at the time of PTH administration or whether it is reduced because of the high-bone-formation phenotype of the SOST null mouse. Coadministration of an anti-SOST treatment and PTH or inducible deletion of sclerostin at the time of PTH administration could resolve this issue.
The two key areas of influence of PTH anabolic action that are clearly blocked in the absence of sclerostin are the increase in osteoclast surface and the increase in cortical thickness. The possibility that osteocytes may regulate osteoclast formation has been suggested recently by the observation that RANKL may be released by osteocytes to initiate osteoclast formation after microfracture.19 The lack of a coupling-associated increase in osteoclast surface even at a very high dose of PTH treatment in SOST null mice provides another link between the osteocyte and the osteoclast, suggesting intriguingly that inhibition of sclerostin is required for the link between increased osteoblast activity and osteoclast formation during PTH treatment.
It has been reported recently that while PTH increases osteoblast number in trabecular bone by inhibiting osteoblast apoptosis, periosteal osteoblasts have a constitutively lower level of apoptosis.20 This regional difference requires that PTH stimulate osteoblast number in cortical and trabecular bone through different mechanisms. The lack of effect of PTH on the cortical bone of SOST null mice may indicate that the cortical mechanism of PTH action is sclerostin-dependent.
What is perhaps surprising is that although sclerostin expression and trabecular and cortical bone volume are grossly abnormal in both these mouse models, PTH is still able to have an anabolic effect. It is clear that sclerostin is not the master regulator of PTH effects in bone, as perhaps it might have been hoped for. But why would it, or any other gene product, provide one major linear pathway downstream of the PTH receptor (PTH1R)? A number of microarray studies of PTH-treated whole bone or osteoblasts have identified thousands of genes regulated by PTH.21–23 Many of these genes have been identified to play a role in PTH anabolic action in studies of knockout mice, including transcription factors ATF418 and CREM24; signaling molecules such as β-arrestin25; cytokines such as fibroblast growth factor 2 (FGF2),16 interleukin 18 (IL-18),15 and insulin-like growth factor 1 (IGF-1)26; matrix proteins including osteonectin27; and other factors that regulate Wnt pathway signaling including secreted Frizzled-related protein 1 (sFRP-1).28, 29 Surprisingly, given the results in SOST transgenic mice, anabolic treatment with PTH was just as effective in the absence of low density lipoprotein receptor-related protein 5 (LRP5) as in wild-type mice.30, 31 This may indicate that the component of the anabolic effect of PTH that is dependent on sclerostin is not dependent on LRP5.
It may be that administration of PTH in an anabolic model reflects the physiologic paracrine action of the other ligand of PTH1R, i.e., PTHrP.32 From this perspective, a modified effect of PTH in SOST null mice also could reflect a contribution of the deleted gene to the paracrine action of PTHrP, which is clearly required for normal bone metabolism.32 The dramatic basal skeletal phenotypes of the SOST overexpressing and SOST null mice, in contrast to the mild skeletal phenotypes of other mice listed earlier, suggest a more prominent contribution of sclerostin to the physiologic effects of PTHrP. The inhibition of sclerostin by other anabolic treatments including mechanical loading33 and treatment with Oncostatin M, Cardiotrophin-1, or Leukemia Inhibitory Factor34 suggest a convergence of a number of anabolic pathways and their (at least partial), dependence on downregulation of sclerostin.
The impact of sclerostin deficiency or overexpression on PTH anabolic effects is worthy of particular note because antisclerostin administration is able to effectively increase bone mass in animal models of estrogen deficiency– and colitis-induced osteopenia,35, 36 suggesting that antisclerostin therapy for osteoporosis is a promising approach. The ability of PTH to increase trabecular bone volume, albeit to a lesser extent in these two mouse models, suggests that while downregulation of sclerostin contributes to the anabolic effect of PTH, other signaling pathways are likely to play a role. In future experiments it would be worth testing combined treatment with PTH and antisclerostin. This also could be guided by studying PTH efficacy in inducible SOST knockouts.
The reduced effectiveness of PTH in the presence of high or absent levels of sclerostin may suggest one explanation for the altered efficacy of PTH in the patient population. Given that single-nucleotide polymorphisms of SOST that predispose to increased fracture risk and low BMD have been identified recently,37–40 the possibility that PTH may be less effective in these populations demands that additional treatment options are made available.
Thanks to Professor TJ Martin for helpful discussions in the preparation of this commentary.
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