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Serum Dickkopf 1 levels in sclerostin deficiency
A H van Lierop1, M J C Moester, N A T Hamdy
1Department of Endocrinology and Metabolic Diseases and Leiden Center for Bone Quality, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Context:
Sclerostin and Dickkopf 1 (DKK1) are antagonists of the canonical Wnt signaling pathway, both binding to the same low-density lipoprotein receptor-related protein 5/6 on osteoblasts, thereby inhibiting bone formation. It is not known whether there is an interaction between sclerostin and DKK1.
Objective:
We examined whether a lack of sclerostin is compensated by increased DKK1 levels.
Design, Setting, And Patients:
We measured DKK1 levels in serum samples of patients and carriers of sclerosteosis (19 patients, 24 carriers) and van Buchem disease (VBD) (13 patients, 22 carriers) and 25 healthy controls. Sclerosteosis and VBD are caused by deficient sclerostin synthesis and are characterized by increased bone formation and hyperostotic phenotypes.
Main Outcome Measures:
DKK1 levels were compared between patients and carriers, and between patients and healthy controls. We also examined associations between levels of DKK1 and the bone turnover markers procollagen type 1 amino-terminal propeptide and carboxy-terminal cross-linking telopeptide.
Results:
We found that DKK1 levels were significantly higher in patients with both sclerosteosis (4.28 ng/mL [95% confidence interval (CI), 3.46-5.11 ng/mL]) and VBD (5.28 ng/mL [95% CI, 3.84-6.71 ng/mL]), compared to levels in carriers of the two diseases (sclerosteosis, 2.03 ng/mL [95% CI, 1.78-2.29 ng/mL], P < .001; VBD, 3.47 ng/mL [95% CI, 2.97-3.97 ng/mL], P = 0.017) and to levels in healthy controls (2.77 ng/mL [95% CI, 2.45-3.08 ng/mL]; P = 0.004 and P < .001, respectively). Serum DKK1 levels were positively associated with levels of procollagen type 1 amino-terminal propeptide and carboxy-terminal cross-linking telopeptide in both disorders.
Conclusions:
These results suggest that increased DKK1 levels observed in patients with sclerosteosis and VBD represent an adaptive response to the increased bone formation characterizing these diseases, although these increased levels do not compensate for the lack of sclerostin on bone formation.
Insights
Higher Dickkopf 1 (DKK1) levels in sclerosteosis and van Buchem disease (VBD) patients suggest an adaptive response to increased bone formation. However, these elevated DKK1 levels do not fully compensate for the lack of sclerostin in bone formation.
Area of Science:
- Bone biology and Wnt signaling pathway research.
- Endocrinology and metabolic bone diseases.
- Genetics of bone disorders.
Background:
- Sclerostin and Dickkopf 1 (DKK1) inhibit bone formation by antagonizing the Wnt signaling pathway.
- Both sclerostin and DKK1 bind to LRP5/6 receptors on osteoblasts.
- The interaction between sclerostin and DKK1 in bone metabolism is not fully understood.
Purpose of the Study:
- To investigate whether a deficiency in sclerostin leads to compensatory increases in DKK1 levels.
- To explore the relationship between sclerostin deficiency, DKK1 levels, and bone turnover markers.
- To understand the adaptive responses in bone formation in sclerostin-deficient conditions.
Main Methods:
- Serum DKK1 levels were measured in patients and carriers of sclerosteosis and van Buchem disease (VBD).
- DKK1 levels were compared between patient groups, carriers, and healthy controls.
- Associations between DKK1 levels and bone turnover markers (P1NP, CTX) were analyzed.
Main Results:
- Patients with sclerosteosis and VBD exhibited significantly higher serum DKK1 levels compared to carriers and healthy controls.
- Serum DKK1 levels were positively correlated with bone turnover markers P1NP and CTX in both sclerosteosis and VBD.
- Elevated DKK1 levels were observed in conditions of sclerostin deficiency.
Conclusions:
- Increased DKK1 levels in sclerosteosis and VBD appear to be an adaptive response to heightened bone formation.
- Despite elevated DKK1, the lack of sclerostin is not fully compensated for in terms of bone formation.
- The findings provide insights into the complex regulation of bone metabolism in sclerostin-related disorders.
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