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Dickkopf-1 negatively regulates the expression of osteoprotegerin, a key osteoclastogenesis inhibitor, by sequestering Lrp6 in primary and metastatic lytic bone lesions

View Article: PubMed Central - PubMed

ABSTRACT

Recently, an inverse role for Wnt signaling in the development of osteoclasts in the bone was demonstrated. In the present study, we examined whether there is a commonality in the mechanism of bone resorption and lysis that occur in a diverse set of bone metastatic lesions, as well as in primary bone lesions. Compared with control bone tissue and bone biopsies from patients with nonmetastatic primary tumors (i.e., breast carcinoma, lung adenocarcinoma, and prostate carcinoma), patients with bone metastatic lesions from the three aforementioned primary tumors, as well as osteolytic lesions obtained from the bone biopsies of patients with multiple myeloma, demonstrated an upregulated expression of the glycoprotein Dickkopf-1 at both the mRNA and protein levels. Additionally, by coimmunoprecipitation, Dickkopf-1 pulled-down low-density lipoprotein receptor-related protein 6 (Lrp6), which is a key downstream effector of the Wnt signaling pathway. The expression of Lrp6 was unaltered in the osteometastatic lesions. This negative regulation was associated with a lowered expression of osteoprotegerin in the osteometastatic lesions, an observation that was previously reported to promote osteoclastogenesis. These findings provide a common mechanism for the inverse relationship between the Wnt signaling pathway and the development of primary or metastatic bone lesions. Pharmacological modulation of the Wnt signaling pathway might benefit the clinical management of primary and metastatic bone lesions.

No MeSH data available.


Western blot showing elevated levels of Dickkopf-1 in the osteometastatic lesions compared with the controls A representative blot is shown here. Triplicate samples were analyzed to obtain the quantitative intensities of the protein signals for Dickkopf-1 and β-actin (the loading control). These means between the groups were different and were statistically significant when examined by analyses of variance (∗P <0.01).
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Figure 2: Western blot showing elevated levels of Dickkopf-1 in the osteometastatic lesions compared with the controls A representative blot is shown here. Triplicate samples were analyzed to obtain the quantitative intensities of the protein signals for Dickkopf-1 and β-actin (the loading control). These means between the groups were different and were statistically significant when examined by analyses of variance (∗P <0.01).

Mentions: Compared with the control bone tissues, the bone metastatic lesions from the breast carcinoma, lung adenocarcinoma, and prostate carcinoma patients, as well as the osteolytic lesions obtained from the bone biopsies of patients with multiple myeloma, demonstrated an upregulated expression of the glycoprotein Dickkopf-1. Representative Western blots are shown in Fig. 2. Triplicate samples were analyzed for obtaining the quantitative intensities of the protein signals. These means between the groups were different and were statistically significant when examined by analyses of variance (P <0.01).


Dickkopf-1 negatively regulates the expression of osteoprotegerin, a key osteoclastogenesis inhibitor, by sequestering Lrp6 in primary and metastatic lytic bone lesions
Western blot showing elevated levels of Dickkopf-1 in the osteometastatic lesions compared with the controls A representative blot is shown here. Triplicate samples were analyzed to obtain the quantitative intensities of the protein signals for Dickkopf-1 and β-actin (the loading control). These means between the groups were different and were statistically significant when examined by analyses of variance (∗P <0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4998439&req=5

Figure 2: Western blot showing elevated levels of Dickkopf-1 in the osteometastatic lesions compared with the controls A representative blot is shown here. Triplicate samples were analyzed to obtain the quantitative intensities of the protein signals for Dickkopf-1 and β-actin (the loading control). These means between the groups were different and were statistically significant when examined by analyses of variance (∗P <0.01).
Mentions: Compared with the control bone tissues, the bone metastatic lesions from the breast carcinoma, lung adenocarcinoma, and prostate carcinoma patients, as well as the osteolytic lesions obtained from the bone biopsies of patients with multiple myeloma, demonstrated an upregulated expression of the glycoprotein Dickkopf-1. Representative Western blots are shown in Fig. 2. Triplicate samples were analyzed for obtaining the quantitative intensities of the protein signals. These means between the groups were different and were statistically significant when examined by analyses of variance (P <0.01).

View Article: PubMed Central - PubMed

ABSTRACT

Recently, an inverse role for Wnt signaling in the development of osteoclasts in the bone was demonstrated. In the present study, we examined whether there is a commonality in the mechanism of bone resorption and lysis that occur in a diverse set of bone metastatic lesions, as well as in primary bone lesions. Compared with control bone tissue and bone biopsies from patients with nonmetastatic primary tumors (i.e., breast carcinoma, lung adenocarcinoma, and prostate carcinoma), patients with bone metastatic lesions from the three aforementioned primary tumors, as well as osteolytic lesions obtained from the bone biopsies of patients with multiple myeloma, demonstrated an upregulated expression of the glycoprotein Dickkopf-1 at both the mRNA and protein levels. Additionally, by coimmunoprecipitation, Dickkopf-1 pulled-down low-density lipoprotein receptor-related protein 6 (Lrp6), which is a key downstream effector of the Wnt signaling pathway. The expression of Lrp6 was unaltered in the osteometastatic lesions. This negative regulation was associated with a lowered expression of osteoprotegerin in the osteometastatic lesions, an observation that was previously reported to promote osteoclastogenesis. These findings provide a common mechanism for the inverse relationship between the Wnt signaling pathway and the development of primary or metastatic bone lesions. Pharmacological modulation of the Wnt signaling pathway might benefit the clinical management of primary and metastatic bone lesions.

No MeSH data available.