ORIGINAL ARTICLE

Endocrine Research

Circulating Sclerostin in Disorders of Parathyroid Gland Function

Aline G. Costa, Serge Cremers, Mishaela R. Rubin, Donald J. McMahon, James Sliney, Jr., Marise Lazaretti-Castro, Shonni J. Silverberg, and John P. Bilezikian

Department of Medicine (A.G.C., S.C., M.R.R., D.J.M., J.S., S.J.S., J.P.B.), Division of Endocrinology,

Metabolic Bone Diseases Unit, College of Physicians and Surgeons, Columbia University, New York, New Downloaded from https://academic.oup.com/jcem/article/96/12/3804/2834946 by guest on 26 September 2021 York 10032; and Department of Medicine (A.G.C., M.L.-C.), Division of Endocrinology, Sa˜ o Paulo Federal University, Sa˜ o Paulo 04044, Brazil

Context: Sclerostin, a encoded by the SOST in and an antagonist of the , is down-regulated by PTH administration. Disorders of parathyroid function are useful clinical settings to study this relationship.

Objective: The objective of the study was to evaluate sclerostin in two different disorders of parathyroid function, primary hyperparathyroidism and hypoparathyroidism, and to analyze the relationship between sclerostin and PTH, bone markers, and bone mineral density.

Design: This is a cross-sectional study.

Setting: The study was conducted at a clinical research center.

Patients: Twenty hypoparathyroid and 20 hyperparathyroid patients were studied and compared to a reference control group.

Results: Serum sclerostin was significantly higher in hypoparathyroid subjects than in hyperparathy- roid subjects (P Ͻ 0.0001) and controls (P Ͻ 0.0001). PTH was negatively associated with sclerostin, achieving statistical significance in hypoparathyroidism (r ϭϪ0.545; P ϭ 0.02). The bone turnover markers, cross-linked C-telopeptide of type I collagen (CTX) and amino-terminal propeptide of type I collagen (P1NP), were differently associated with sclerostin according to the parathyroid disorder. In primary hyperparathyroidism, bone turnover markers were associated negatively with sclerostin (for P1NP, r ϭϪ0.490; P ϭ 0.03). In hypoparathyroidism, bone turnover markers were associated positively with sclerostin (for CTX, r ϭϩ0.571; P ϭ 0.01). Although there was no significant correlation between bone mineral density and sclerostin in either parathyroid disorder, there was a significant positive relationship between sclerostin and bone mineral content in hypoparathyroidism.

Conclusions: The results are consistent with the hypothesis that PTH is a regulator of sclerostin in human disorders of parathyroid function. In addition, the results suggest that bone mineral content may be another factor that influences sclerostin. (J Clin Endocrinol Metab 96: 3804–3810, 2011)

clerostin is a secretory product of the , the mental influences, the osteocyte signals the two other key S most abundant cell in the skeleton (1, 2). Long con- bone cells, the and the osteoclast, by producing sidered to be an outdated osteoblast, inactive and “en- molecules such as sclerostin (3–5). tombed” in the mineralized matrix of bone, the osteocyte Sclerostin, a glycoprotein encoded by the osteocyte is now acknowledged to be a master skeletal signaling cell. SOST gene, regulates the activities of the mature osteo- Responding to mechanical stress and to other environ- blast as well as the osteoblast lineage pathway. Inactivat-

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: BAP, Bone-specific alkaline phosphatase; BMC, bone mineral content; BMD, Printed in U.S.A. bone mineral density; CTX, cross-linked C-telopeptide of type I collagen; DXA, dual-energy Copyright © 2011 by The Endocrine Society x-ray absorptiometry; FN, femoral neck; HypoPT, hypoparathyroidism; LS, lumbar spine; 25- doi: 10.1210/jc.2011-0566 Received March 3, 2011. Accepted August 29, 2011. OHD, 25-hydroxyvitamin D; PHPT, primary hyperparathyroidism; P1NP, serum amino-terminal First Published Online September 20, 2011 propeptide of type I collagen; 1/3 radius, one third distal radius; TH, total hip.

3804 jcem.endojournals.org J Clin Endocrinol Metab, December 2011, 96(12):3804–3810 J Clin Endocrinol Metab, December 2011, 96(12):3804–3810 jcem.endojournals.org 3805 ing mutations of the SOST gene lead to exuberant bone Serum measurements growth, as demonstrated in the human disorders scleros- Blood samples were prepared, and sera were immediately Ϫ teosis and van Buchem’s disease (6–9). Affected individ- frozen at 70 C. Serum sclerostin levels were measured using an ELISA developed by TECOmedical Group. This ELISA uses a uals have exceedingly dense bones as assessed by radio- biotinylated polyclonal as well as a horseradish per- graphic and dual-energy x-ray absorptiometry (DXA) oxidase-labeled secondary monoclonal antibody that specifi- measurements, but they are of normal quality, and frac- cally recognizes human sclerostin. The detection limit of the as- tures have not been reported. A phenotype similar to say is 0.15 ng/ml. No study subjects demonstrated sclerostin sclerosteosis is seen in a mouse Sost knockout model (10). levels below this detection limit. Intra- and interassay precision Sclerostin’s control of osteoblast action and develop- are 1.6 and 2.7%, respectively. Results for the sclerostin mea- surements are reported throughout in nanograms per milliliter ment is mediated by the anabolic Wnt and BMP signaling (multiply by 44 to convert to picomoles per liter). Downloaded from https://academic.oup.com/jcem/article/96/12/3804/2834946 by guest on 26 September 2021 pathways. By binding to the LRP5/LRP6 receptor com- PTH was measured in duplicate using the immunoradiomet- plex, sclerostin inhibits the activity of molecules such as ric assay for the quantitative determination of human total intact the Wnt pathway’s ␤-catenin, a major activator of ana- PTH as developed by Scantibodies Laboratories, Inc. (Santee, bolic in the nucleus of the osteoblast (2, 11–14). CA). Normal range is 14–66 pg/ml. Interassay precision is 8.4%, and the intraassay precision is 5.7%. Serum amino-terminal pro- Sclerostin also has been shown to inhibit BMP7 secretion peptide of type I collagen (P1NP), cross-linked C-telopeptide of by osteocytes in mice (15). type I collagen (CTX), and 25-hydroxyvitamin D (25-OHD) PTH has increasingly been implicated as one of the were measured simultaneously by immunochemiluminescence factors involved in the regulation of sclerostin (16). Evi- assays on the IDS-iSYS Multi-Discipline automated analyzer dence that PTH regulates sclerostin expression comes (Immunodiagnostics Systems, Scottsdale, AZ). Normal range for P1NP is 27.7–127.6 ng/ml. Sensitivity is below 1 ng/ml, and from human and animal studies at both the cellular and intra- and interassay precision are below 4% and below 6%, molecular level (17–20). Diseases characterized by exces- respectively. Dynamic range for CTX is 0.033–6.000 ng/ml, and sive or deficient PTH provide a useful model to further intra- and interassay precision is 4.9 and 8.8%, respectively. explore the relationship between PTH and sclerostin. In Normal reference values for 25-OHD are set at above 30 ng/ml, this study, we measured circulating sclerostin levels in pa- with sensitivity of 5.5 ng/ml and intra- and interassay precision tients with overproduction or deficient PTH, namely pri- of below 8% and below 10%, respectively. mary hyperparathyroidism (PHPT) or hypoparathyroid- Bone mineral density (BMD) ism (HypoPT). BMD was measured at the lumbar spine (LS; L1–L4), total hip (TH), femoral neck (FN), and distal one-third radius (1/3 radius) by DXA (Hologic 4500W; Hologic Inc., Bedford, MA). The Subjects and Methods short-term in vivo precision error (root-mean-square SD) was 0.026 g/cm2 for L1–L4, 0.032 g/cm2 for the TH, 0.041 g/cm2 for Subjects the FN, and 0.033 g/cm2 for the forearm. Serum samples were obtained from ongoing HypoPT and PHPT studies at the Metabolic Bone Diseases Unit of Columbia Statistical analysis University Medical Center. A convenience sample consisting Results are expressed as mean Ϯ SEM. Serum chemistry mea- of 20 subjects (10 postmenopausal women and 10 men) with sures were log-transformed before analysis, and tests were ad- HypoPT and 20 subjects (10 postmenopausal women and 10 justed for age and unequal variances when appropriate. HypoPT men) with PHPT was chosen. HypoPT was defined as chronic and PHPT groups were evaluated by two-sided independent t- hypocalcemia in association with levels of PTH below the PTH tests. Each clinical group was compared with controls by inde- assay reference range (Ͻ10 pg/ml). PHPT was defined by hyper- pendent t-test also. Pearson correlations were used to assess the calcemia in association with levels of PTH in the upper range or association between sclerostin and bone mineral indices. Linear above the PTH assay reference range (Ͼ65 pg/ml). Exclusion regression was used to fit a least squares prediction line between criteria included: liver or kidney disease, Paget’s disease, rheu- sclerostin (log10) and CTX (log10) and P1NP (log10) separately matoid arthritis, diabetes mellitus, Cushing’s syndrome, multi- for each group. A value of P Ͻ 0.05 was considered significant. ple myeloma or any other malignancy, current treatment with Statistical analysis was performed using SAS, version 9.2 (SAS any , glucocorticoids, , raloxifene, es- Institute, Inc., Cary, NC). trogens, fluoride, lithium, or methotrexate. Serum was obtained, and DXA measurements were made before any patient under- went pharmacological (PTH for HypoPT) or surgical (parathy- Results roidectomy for PHPT) treatment for their disease. Sclerostin se- rum of 31 healthy subjects (15 men and 16 postmenopausal Baseline biochemical and DXA data women; age range, 37 to 79 yr) were used as the control group Demographic data are shown in Table 1. HypoPT and (provided by TECOmedical AG, Sissach, Switzerland). The study was approved by the Institutional Review Board of Co- PHPT subjects were of similar age and body mass index. lumbia University Medical Center, and all subjects gave written As expected, PTH levels were much lower in the HypoPT informed consent. group (7.3 Ϯ 0.9 pg/ml) than in the PHPT group (91.9 Ϯ 3806 Costa et al. Sclerostin and Parathyroid Disorders J Clin Endocrinol Metab, December 2011, 96(12):3804–3810

TABLE 1. Baseline characteristics, biochemical indices, TABLE 2. Serum sclerostin and BMD measurements HypoPT PHPT Controls HypoPT PHPT P value All 1.118 Ϯ 0.09a,b 0.656 Ϯ 0.04a 0.715 Ϯ 0.04b c,d c d Age (yr) 58.3 Ϯ 1.4 59.2 Ϯ 1.4 NS Female 0.859 Ϯ 0.05 0.670 Ϯ 0.05 0.648 Ϯ 0.05 a,b a c BMI (kg/m2) 28.6 Ϯ 1.2 25.8 Ϯ 1.2 NS Males 1.376 ؎ 0.14 0.643 Ϯ 0.07 0.802 Ϯ 0.08 Intact PTH (pg/ml) 7.3 Ϯ 0.9 91.9 Ϯ 13.1 Ͻ0.0001 Data are expressed as mean (ng/ml) Ϯ SEM, and P values were 25-OHD (ng/ml) 52 Ϯ 5 32.8 Ϯ 3 0.002 Ϯ Ϯ Ͻ calculated on log-transformed data (see Statistical analysis). Male data Calcium (mg/dl) 8.5 0.2 10.6 0.2 0.0001 higher than females are shown in bold. CTX (ng/ml) 0.110 Ϯ 0.01 0.780 Ϯ 0.13 Ͻ0.0001 a P1NP (ng/ml) 22.7 Ϯ 2 55.9 Ϯ 8 Ͻ0.0001 P Ͻ 0.0001 HypoPT vs. PHPT. LS BMD (g/cm2) 1.201 Ϯ 0.05 0.847 Ϯ 0.03 Ͻ0.0001 b P Ͻ 0.0001 HypoPT vs. control. 2 Ϯ Ϯ Downloaded from https://academic.oup.com/jcem/article/96/12/3804/2834946 by guest on 26 September 2021 TH BMD (g/cm ) 1.027 0.05 0.826 0.03 0.0013 c P Ͻ 0.05 HypoPT vs. PHPT. FN BMD (g/cm2) 0.863 Ϯ 0.04 0.654 Ϯ 0.02 Ͻ0.0001 d Ͻ 1/3 radius BMD 0.738 Ϯ 0.02 0.673 Ϯ 0.02 Ͻ0.05 P 0.05 HypoPT vs. control. (g/cm2) reflects higher levels of sclerostin in men vs. HypoPT Data are expressed as mean Ϯ SEM (n ϭ 20 per group). Normal ranges are given in the text. BMI, Body mass index; NS, not significant. women. In PHPT subjects, sclerostin levels were lower than controls but the difference was small. There was no 13.1 pg/ml). Also as expected, since vitamin D supple- gender difference in PHPT or in controls (Table 2). mentation is a key part of treatment for HypoPT and 25- PTH and serum sclerostin showed negative associa- OHD metabolism in the kidney by 25-hydroxyvitamin tions in HypoPT and in PHPT with the r-value in the D-1␣-hydroxylase is influenced by PTH and therefore in HypoPT group achieving significance (r ϭϪ0.545, P ϭ PHPT is typically metabolized at a faster rate, 25-OHD 0.02). The slopes of the relationships did not significantly concentrations were higher in HypoPT than in PHPT (P ϭ differ between the 2 diseases (Fig. 2). In PHPT, there was 0.002). In HypoPT, CTX and P1NP concentrations were a significant negative correlation between serum calcium significantly lower than in PHPT (P Ͻ 0.001) reflecting concentration and sclerostin (r ϭϪ0.546; P ϭ 0.02). lower and higher bone turnover rates respectively. BMD at The association between serum sclerostin and bone all sites was greater in HypoPT than in PHPT (Table 1). turnover markers, CTX and P1NP, differed according to the parathyroid disorder. In PHPT, as expected, there was Sclerostin measurements an inverse association between the markers and sclerostin, Serum sclerostin levels were much higher in HypoPT with the r-value between sclerostin and P1NP achieving than in PHPT and normal controls (Fig. 1). Both genders statistical significance (r ϭϪ0.490, P ϭ 0.03; Fig. 3). CTX demonstrated significantly higher levels of sclerostin in and P1NP values were significantly associated with each HypoPT but the comparisons in men (P Ͻ 0.0001) were other (r ϭϩ0.846, P Ͻ 0.001). In HypoPT subjects, while greater than in women (P Ͻ 0.05). This observation bone markers were also significantly associated with each other (r ϭϩ0.627, P ϭ 0.004), serum sclerostin levels, unexpectedly, were correlated positively with CTX and P1NP. The positive relationship between sclerostin and CTX achieved statistical significance (r ϭϩ0.571, P ϭ

FIG. 1. Serum sclerostin levels (mean Ϯ SEM) in HypoPT vs. PHPT and normal controls. ***, P Ͻ 0.0001. P values were calculated on log- transformed data (see Statistical analysis). FIG. 2. Relationship between PTH and sclerostin in HypoPT and PHPT. J Clin Endocrinol Metab, December 2011, 96(12):3804–3810 jcem.endojournals.org 3807

lation between bone marrow plasma and serum concen- trations of sclerostin. Thus, it is likely that although sclerostin is a locally active signaling molecule, circulating levels are of clinical relevance. Human and animal studies have shown that PTH reg- ulates sclerostin expression (17–20, 24). The relationship is primarily a negative one with levels of sclerostin reduced in the presence of PTH (17–20, 22). In this report, we took advantage of two disorders of parathyroid function, HypoPT and PHPT, to explore this relationship to a greater extent than has previously been reported. In a di- Downloaded from https://academic.oup.com/jcem/article/96/12/3804/2834946 by guest on 26 September 2021 rect comparison between HypoPT and PHPT, we have shown that sclerostin levels are much higher in HypoPT than in PHPT. HypoPT subjects also demonstrate much higher levels of sclerostin than control subjects. The cor- relation between sclerostin and PTH in PHPT was not significant, although the slopes of the sclerostin-PTH re- lationships were identical, suggesting that the lack of a significant relationship may relate to the limited number of subjects with PHPT we studied. A relationship between sclerostin and PTH in PHPT was recently shown by Kaji et al. (26). Moreover, Drake et al. (20) have demonstrated that sclerostin levels fell 14 d after PTH exposure. The observations are consistent with our current understand- ing that PTH is a negative regulator of sclerostin. Consis- tent with this point, in PHPT, sclerostin levels are lower than controls but the difference did not achieve statistical significance. Our data, nevertheless, are in agreement with the report of Lierop et al. (24), who demonstrated signif- FIG. 3. Relationship between sclerostin and the bone formation marker P1NP (A) and the bone resorption marker CTX (B) in HypoPT icantly lower sclerostin levels in PHPT than in controls. and PHPT. Similar to our study, there was substantial overlap in val- ues between groups. The more dramatic difference in sclerostin levels in Hy- 0.01; Fig. 3). No significant correlation was seen between poPT vs. PHPT subjects may reflect the fact that the cat- sclerostin and daily supplemental intake of calcium, cal- abolic actions of PTH predominate in PHPT. In this set- citriol and vitamin D in the HypoPT. ting, therefore, PTH is likely to be preferentially using its There was no association between serum sclerostin and catabolic receptor activator of nuclear factor ␬B ligand- BMD at any site in HypoPT or PHPT, but a strong and mediated biochemical pathway and not the sclerostin-me- significant correlation was seen between sclerostin with bone mineral content (BMC) in HypoPT subjects (LS diated Wnt-signaling pathway associated with its anabolic BMC, r ϭϩ0.648, P ϭ 0.003; TH BMC, r ϭϩ0.663, P ϭ actions (27, 28). Hence, in PHPT, PTH may have a smaller 0.002; FN BMC, r ϭϩ0.778, P Ͻ 0.0001; and 1/3 radius effect on sclerostin than it would have in another situation BMC, r ϭϩ0.643, P ϭ 0.003) (Fig. 4). such as when PTH is used as an anabolic therapy for os- teoporosis. Consistent with this hypothesis, the negative relationship between sclerostin and PTH was stronger in ϭϪ ϭ Discussion the HypoPT subjects (r 0.545; P 0.02) than in the PHPT subjects (r ϭϪ0.316; P ϭ 0.2). These results confirm and extend recent studies of serum Another noteworthy feature of this report is the rela- sclerostin in the circulation of patients with several dif- tionship between sclerostin and bone turnover markers. ferent metabolic bone diseases (21–24). These studies have Previous studies, which have analyzed the relationship be- been enabled by the availability of validated assays for tween sclerostin levels and circulating markers of bone sclerostin (25), an advance over earlier approaches (17– turnover, have not been consistent (20, 22–24, 29). Mo¨d- 19). Drake et al. (20) recently showed a significant corre- der et al. (29) noted a negative correlation between bone 3808 Costa et al. Sclerostin and Parathyroid Disorders J Clin Endocrinol Metab, December 2011, 96(12):3804–3810

(31), subjects who received a single sc dose of the sclerostin monoclonal anti- body (AMG 785) demonstrated not only an increase in bone formation markers (maximum percentage change with 10 mg/kg dose sc, P1NP, ϩ184%; BAP, ϩ126%; and osteocalcin, ϩ176%) but also a decrease in bone resorption marker CTX (Ϫ54%). Surprisingly, in HypoPT the corre-

lation between sclerostin and bone Downloaded from https://academic.oup.com/jcem/article/96/12/3804/2834946 by guest on 26 September 2021 turnover markers is a positive one. At this point, a clear understanding of this relationship is not apparent, but several possibilities come to mind. The higher levels of sclerostin in the setting of low levels of bone turnover markers could reflect a secondary or compensatory ef- fect of sclerostin in response to inde- pendent non-PTH factors such as bone mass. Another explanation is that PTH may act as a necessary facilitator for the inhibitory action of sclerostin on bone formation. In the absence of PTH, sclerostin might be permissive and un- able to serve as a regulatory molecule. Recent data by Rhee et al. (32) are con- sistent with this concept. Mice overex- pressing sclerostin with a constitutively active PTH 1 receptor in osteocytes have lower BMD compared with mice overexpressing sclerostin only. Consis- tent with this idea, fibroblast growth

FIG. 4. Relationship between sclerostin and BMD (A) and BMC (B) in HypoPT and PHPT. factor-23, another osteocyte-driven cell product, requires a threshold PTH level in order for it to be functional (33, 34). formation [bone-specific alkaline phosphatase (BAP), Mo¨ dder et al. (29) have reported that men have higher P1NP] and bone resorption (CTX) markers only in post- sclerostin levels than women. We were able to show a menopausal women at least 60 yr old. In another study by higher level of sclerostin only in male HypoPT subjects. Gaudio et al. (23), sclerostin was negatively associated Although consistent with the reports of Mo¨ dder et al. (29) with BAP but positively associated with CTX. However, and Schett and Hennies (25), our data did not universally several other studies have not shown a significant rela- tionship between bone turnover markers and sclerostin confirm these findings in PHPT and in controls. Perhaps levels (22, 24, 30). Our study provides additional insight this could be accounted for by our relatively small sam- into this issue, with results that suggest that these rela- ple size. tionships are influenced by the parathyroid disorder. As Published data on a correlation between BMD and cir- expected, in PHPT, a negative relationship was seen be- culating sclerostin are also inconsistent. Mirza et al. (22) tween sclerostin and CTX and between sclerostin and found a negative correlation between femoral neck BMD P1NP. The effect was greater on P1NP than on CTX. The and sclerostin in all subjects (pre- and postmenopausal greater effect of sclerostin on an index of bone formation women), but after adjustment for age, the relationship was than one of bone resorption is consistent with recent stud- no longer significant. Mo¨ dder et al. (29) performed a total ies of sclerostin in which bone formation mark- body scan in a population-based sample of 362 patients ers are markedly increased (31). In the study of Padhi et al. and found a positive association between total body bone J Clin Endocrinol Metab, December 2011, 96(12):3804–3810 jcem.endojournals.org 3809 mass and total body BMC with circulating sclerostin in S, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, Stratakis C, Lind- middle-aged and elderly subjects, but not in the younger paintner K, Vickery B, Foernzler D, Van Hul W 2001 Increased bone density in sclerosteosis is due to the deficiency of a novel secreted population. Polyzos et al. (30) have also noted a positive protein (SOST). Hum Mol Genet 10:537–543 correlation with LS BMD and T-score. A positive associ- 7. Wergedal JE, Veskovic K, Hellan M, Nyght C, Balemans W, Liba- ation between sclerostin and BMD is rather paradoxical nati C, Vanhoenacker FM, Tan J, Baylink DJ, Van Hul W 2003 because sclerostin plays a regulatory role in bone miner- Patients with van Buchem disease, an osteosclerotic genetic disease, have elevated bone formation markers, higher bone density, and alization by inhibiting osteoblastic activity. greater derived polar moment of inertia than normal. J Clin Endo- Although we did not find a correlation between scleros- crinol Metab 88:5778–5783 tin and BMD in either group, we found a strong positive 8. Hamersma H, Gardner J, Beighton P 2003 The natural history of sclerosteosis. Clin Genet 63:192–197 correlation between sclerostin and BMC at all four sites 9. van Bezooijen RL, ten Dijke P, Papapoulos SE, Lo¨ wik CW 2005 (LS, FN, TH, and 1/3 radius) in HypoPT but not in PHPT. SOST/sclerostin, an osteocyte-derived negative regulator of bone Downloaded from https://academic.oup.com/jcem/article/96/12/3804/2834946 by guest on 26 September 2021 The correlation between BMC and sclerostin was sus- formation. Cytokine Growth Factor Rev 16:319–327 tained after adjustment for PTH levels. In addition to 10. Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D’Agostin D, Kurahara C, Gao Y, Cao J, Gong J, Asuncion F, Barrero M, Warm- PTH, then, the results suggest that BMC may be another ington K, Dwyer D, Stolina M, Morony S, Sarosi I, Kostenuik PJ, one of several factors that influence sclerostin. It is likely Lacey DL, Simonet WS, Ke HZ, Paszty C 2008 Targeted deletion of that higher BMC is associated with more numerous os- the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869 teocytes and that osteocyte number drives this relation- 11. Seme¨nov M, Tamai K, He X 2005 SOST is a ligand for LRP5/LRP6 ship. With further studies, the nature of these relationships and a Wnt signaling inhibitor. J Biol Chem 280:26770–26775 between sclerostin, PTH, and bone mass will become more 12. van Bezooijen RL, Svensson JP, Eefting D, Visser A, van der Horst apparent. G, Karperien M, Quax PH, Vrieling H, Papapoulos SE, ten Dijke P, Lo¨ wik CW 2007 Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. J Bone Miner Res 22:19–28 Acknowledgments 13. Johnson ML, Kamel MA 2007 The Wnt signaling pathway and bone metabolism. Curr Opin Rheumatol 19:376–382 We thank Marieluise Wippermann (TECOmedical Group) for 14. Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D 2005 Sclerostin binds to LRP5/6 and antagonizes canonical Wnt providing us with the sclerostin assay materials. signaling. J Biol Chem 280:19883–19887 15. Krause C, Korchynskyi O, de Rooij K, Weidauer SE, de Gorter DJ, Address all correspondence and requests for reprints to: John van Bezooijen RL, Hatsell S, Economides AN, Mueller TD, Lo¨ wik P. Bilezikian, M.D., Department of Medicine, College of Physi- CW, ten Dijke P 2010 Distinct modes of inhibition by sclerostin on cians and Surgeons, 630 West 168th Street, PH 8 West, Room bone morphogenetic protein and Wnt signaling pathways. J Biol 864, New York, New York 10032. E-mail: [email protected]. Chem 285:41614–41626 This work was supported by Grants DK32333, DK06950, 16. Kramer I, Keller H, Leupin O, Kneissel M 2010 Does osteocytic DK066329, and K24DK074457 from the National Institutes of SOST suppression mediate PTH bone anabolism? Trends Endocri- Health and by Grant FD002525 from the Food and Drug nol Metab 21:237–244 Administration. 17. Keller H, Kneissel M 2005 SOST is a target gene for PTH in bone. Disclosure Summary: The authors have nothing to disclose. Bone 37:148–158 18. 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