Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression

Heiland, Gisela Ruiz; Zwerina, Karin; Baum, Wolfgang; Kireva, Trayana; Distler, Jörg H W; Grisanti, Mario; Asuncion, Frank; Li, Xiadong; Ominsky, Michael S.; Richards, William G.; Schett, Georg; Zwerina, Jochen

doi:10.1136/ard.2010.132852

Cited by 189 publications

(164 citation statements)

References 32 publications

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“…Since TNF-a seemed to increase the levels of other canonical Wnt proteins, we investigated the activation of the canonical Wnt signaling pathway with anti-Dkk1 antibodies. Stimulatory effects of anti-Dkk1 antibodies have recently been reported in mouse primary osteoblasts [17], and are consistent with the beneficial effects of anti-Dkk1 antibodies on bone formation in vivo [10,17,35,36]. In our experiments, blocking Dkk1 slightly increased TNAP expression in osteoblasts differentiating from human MSCs.…”

Section: Discussionsupporting

confidence: 92%

“…In addition to its role in physiological bone remodeling, Dkk1 likely plays an important role in the inflammatory effects of TNF-a. Indeed, neutralization of Dkk1 activity in TNF-a transgenic mice switches the RA phenotype of these mice into a phenotype resembling to AS [10], and prevents TNF-mediated impaired osteoblast function [17]. Moreover, levels of functional Dkk1 predicts protection from syndesmophyte formation in patients with AS [18].…”

Section: Introductionmentioning

confidence: 99%

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Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human mesenchymal stem cells

Briolay

Lencel²,

Bessueille

et al. 2013

Biochemical and Biophysical Research Communications

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a b s t r a c tAlthough anti-tumor necrosis factor (TNF)-a treatments efficiently block inflammation in ankylosing spondylitis (AS), they are inefficient to prevent excessive bone formation. In AS, ossification seems more prone to develop in sites where inflammation has resolved following anti-TNF therapy, suggesting that TNF-a indirectly stimulates ossification. In this context, our objectives were to determine and compare the involvement of Wnt proteins, which are potent growth factors of bone formation, in the effects of TNF-a on osteoblast function. In human mesenchymal stem cells (MSCs), TNF-a significantly increased the levels of Wnt10b and Wnt5a. Associated with this effect, TNF-a stimulated tissue-non specific alkaline phosphatase (TNAP) and mineralization. This effect was mimicked by activation of the canonical bcatenin pathway with either anti-Dkk1 antibodies, lithium chloride (LiCl) or SB216763. TNF-a reduced, and activation of b-catenin had little effect on expression of osteocalcin, a late marker of osteoblast differentiation. Surprisingly, TNF-a failed to stabilize b-catenin and Dkk1 did not inhibit TNF-a effects. In fact, Dkk1 expression was also enhanced in response to TNF-a, perhaps explaining why canonical signaling by Wnt10b was not activated by TNF-a. However, we found that Wnt5a also stimulated TNAP in MSCs cultured in osteogenic conditions, and increased the levels of inflammatory markers such as COX-2. Interestingly, treatment with anti-Wnt5a antibodies reduced endogenous TNAP expression and activity. Collectively, these data suggest that increased levels of Dkk1 may blunt the autocrine effects of Wnt10b, but not that of Wnt5a, acting through non-canonical signaling. Thus, Wnt5a may be potentially involved in the effects of inflammation on bone formation.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human mesenchymal stem cells

Briolay

Lencel²,

Bessueille

et al. 2013

Biochemical and Biophysical Research Communications

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“…One possible mechanism, in addition to the direct effects of decreasing Dkk1 inhibition of skeletal Wnt activity, is that Dkk1 neutralization affected osteocytic production of sclerostin, another Wnt inhibitor that is increased in early CKD, which is shown here in Figure 9 and the work by Sabbagh et al 15 Sclerostin is a powerful inhibitor of bone formation. 59,60 Our data shown in Figure 6B, which show that Dkk1 neutralization decreases circulating sclerostin levels, are compatible with the demonstration that it protects from systemic bone loss during inflammation in the work by Heiland et al, 61 which also showed that it reduced sclerostin expression. Interestingly, the binding sites of Dkk1 and sclerostin on LDL receptor-related protein 5 and 6 and Kremen differ, perhaps explaining why the actions of these Wnt inhibitors may differ and not be totally redundant.…”

Section: Discussionsupporting

confidence: 87%

CKD-Induced Wingless/Integration1 Inhibitors and Phosphorus Cause the CKD–Mineral and Bone Disorder

Fang¹,

Ginsberg

Seifert

et al. 2014

Journal of the American Society of Nephrology

149

186

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In chronic kidney disease, vascular calcification, renal osteodystrophy, and phosphate contribute substantially to cardiovascular risk and are components of CKD-mineral and bone disorder (CKD-MBD). The cause of this syndrome is unknown. Additionally, no therapy addresses cardiovascular risk in CKD. In its inception, CKD-MBD is characterized by osteodystrophy, vascular calcification, and stimulation of osteocyte secretion. We tested the hypothesis that increased production of circulating factors by diseased kidneys causes the CKD-MBD in diabetic mice subjected to renal injury to induce stage 2 CKD (CKD-2 mice). Compared with non-CKD diabetic controls, CKD-2 mice showed increased renal production of Wnt inhibitor family members and higher levels of circulating Dickkopf-1 (Dkk1), sclerostin, and secreted klotho. Neutralization of Dkk1 in CKD-2 mice by administration of a monoclonal antibody after renal injury stimulated bone formation rates, corrected the osteodystrophy, and prevented CKD-stimulated vascular calcification. Mechanistically, neutralization of Dkk1 suppressed aortic expression of the osteoblastic transcription factor Runx2, increased expression of vascular smooth muscle protein 22-a, and restored aortic expression of klotho. Neutralization of Dkk1 did not affect the elevated plasma levels of osteocytic fibroblast growth factor 23 but decreased the elevated levels of sclerostin. Phosphate binder therapy restored plasma fibroblast growth factor 23 levels but had no effect on vascular calcification or osteodystrophy. The combination of the Dkk1 antibody and phosphate binder therapy completely treated the CKD-MBD. These results show that circulating Wnt inhibitors are involved in the pathogenesis of CKD-MBD and that the combination of Dkk1 neutralization and phosphate binding may have therapeutic potential for this disorder. CKD is a pandemic affecting 26 million Americans in its early stages. 1 CKD is associated with high rates of cardiovascular mortality, making it much more likely that affected individuals will sustain cardiovascular morbidity, including death, than reach end stage kidney disease that requires RRT.

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“…There is a possibility that these Wnt inhibitors themselves participate in such regulation. Evidence of such interactions has been presented in studies of a model of bone loss due to inflammation in which it was reported that antibodies against DKK1 prevented TNF-␣-induced up-regulation of sclerostin expression (48).…”

Section: Effects Of Sci-and Es-induced Muscle Contraction On Wntmentioning

confidence: 99%

The Central Nervous System (CNS)-independent Anti-bone-resorptive Activity of Muscle Contraction and the Underlying Molecular and Cellular Signatures

Qin

Sun

Cao

et al. 2013

Journal of Biological Chemistry

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Background: Mechanisms by which muscle regulates bone are poorly understood. Results: Electrically stimulated muscle contraction reversed elevations in bone resorption and increased Wnt signaling in bone-derived cells after spinal cord transection. Conclusion: Muscle contraction reduced resorption of unloaded bone independently of the CNS, through mechanical effects and, potentially, nonmechanical signals (e.g. myokines). Significance: The study provides new insights regarding muscle-bone interactions.

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Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression

Cited by 189 publications

References 32 publications

Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human mesenchymal stem cells

Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human mesenchymal stem cells

CKD-Induced Wingless/Integration1 Inhibitors and Phosphorus Cause the CKD–Mineral and Bone Disorder

The Central Nervous System (CNS)-independent Anti-bone-resorptive Activity of Muscle Contraction and the Underlying Molecular and Cellular Signatures

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