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Hydroxycoumarin Scopoletin Inhibits Bone Loss through Enhancing Induction of Bone Turnover Markers in a Mouse Model of Type 2 Diabetes

Diabetes induces bone deterioration, which leads to increased risk of fracture, osteopenia, and osteoporosis. Thus, diabetes-associated bone fragility has been recognized as a diabetic complication. However, the pathophysiological effects of hyperglycemia on bone turnover remain unclear. Literature...

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Autores principales: Lee, Eun-Jung, Na, Woojin, Kang, Min-Kyung, Kim, Yun-Ho, Kim, Dong-Yeon, Oh, Hyeongjoo, Kim, Soo-Il, Oh, Su-Yeon, Park, Sohyun, Park, Kyungho, Kang, Young-Hee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227109/
https://www.ncbi.nlm.nih.gov/pubmed/34200167
http://dx.doi.org/10.3390/biomedicines9060648
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author Lee, Eun-Jung
Na, Woojin
Kang, Min-Kyung
Kim, Yun-Ho
Kim, Dong-Yeon
Oh, Hyeongjoo
Kim, Soo-Il
Oh, Su-Yeon
Park, Sohyun
Park, Kyungho
Kang, Young-Hee
author_facet Lee, Eun-Jung
Na, Woojin
Kang, Min-Kyung
Kim, Yun-Ho
Kim, Dong-Yeon
Oh, Hyeongjoo
Kim, Soo-Il
Oh, Su-Yeon
Park, Sohyun
Park, Kyungho
Kang, Young-Hee
author_sort Lee, Eun-Jung
collection PubMed
description Diabetes induces bone deterioration, which leads to increased risk of fracture, osteopenia, and osteoporosis. Thus, diabetes-associated bone fragility has been recognized as a diabetic complication. However, the pathophysiological effects of hyperglycemia on bone turnover remain unclear. Literature evidence demonstrates that anti-diabetic medications increase the risk of fractures in individuals with type 2 diabetes. Scopoletin is a naturally occurring hydroxycoumarin potentially exhibiting anti-inflammatory and antioxidant activities and ameliorating insulin resistance as an anti-diabetic agent. However, little is known regarding the effects of scopoletin on the impairment of bone remodeling that is caused by diabetes. The aim of this study was to identify that scopoletin was capable of inhibiting the impairment of bone remodeling and turnover in a mouse model of type 2 diabetes. Submicromolar scopoletin accelerated the formation TRAP-positive multinucleated osteoclasts (40.0 vs. 105.1%) and actin ring structures impaired by 33 mM glucose. Further, 1–20 μM scopoletin enhanced bone resorption and the induction of matrix-degrading enzymes in diabetic osteoclasts. The oral administration of 10 mg/kg scopoletin elevated serum RANKL/OPG ratio and osteocalcin level reduced in db/db mice along with an increase in BMD by ~6–14%; however, it was not effective in lowering blood glucose and hemoglobin glycation. In addition, the supplementation of scopoletin elevated the formation of trabecular bones and collagen fibers in femoral epiphysis and metaphysis with a thicker epiphyseal plate and cortical bones. Furthermore, 1–20 μM scopoletin enhanced ALP activity (4.39 vs. 7.02 nmol p-nitrophenyl phosphate/min/mg protein) and deposits of mineralized bone nodules in cultured osteoblasts reduced by 33 mM glucose. The treatment of diabetic osteoblasts with scopoletin stimulated the cellular induction of BMP-2 and osteopontin and Runx2 transcription. Accordingly, the administration of scopoletin protected mice from type 2 diabetes-associated bone loss through boosting bone remodeling via the robust induction of bone turnover markers of both osteoclasts and osteoblasts. These findings suggest that scopoletin could be a potential osteoprotective agent for the treatment of diabetes-associated bone loss and fractures.
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spelling pubmed-82271092021-06-26 Hydroxycoumarin Scopoletin Inhibits Bone Loss through Enhancing Induction of Bone Turnover Markers in a Mouse Model of Type 2 Diabetes Lee, Eun-Jung Na, Woojin Kang, Min-Kyung Kim, Yun-Ho Kim, Dong-Yeon Oh, Hyeongjoo Kim, Soo-Il Oh, Su-Yeon Park, Sohyun Park, Kyungho Kang, Young-Hee Biomedicines Article Diabetes induces bone deterioration, which leads to increased risk of fracture, osteopenia, and osteoporosis. Thus, diabetes-associated bone fragility has been recognized as a diabetic complication. However, the pathophysiological effects of hyperglycemia on bone turnover remain unclear. Literature evidence demonstrates that anti-diabetic medications increase the risk of fractures in individuals with type 2 diabetes. Scopoletin is a naturally occurring hydroxycoumarin potentially exhibiting anti-inflammatory and antioxidant activities and ameliorating insulin resistance as an anti-diabetic agent. However, little is known regarding the effects of scopoletin on the impairment of bone remodeling that is caused by diabetes. The aim of this study was to identify that scopoletin was capable of inhibiting the impairment of bone remodeling and turnover in a mouse model of type 2 diabetes. Submicromolar scopoletin accelerated the formation TRAP-positive multinucleated osteoclasts (40.0 vs. 105.1%) and actin ring structures impaired by 33 mM glucose. Further, 1–20 μM scopoletin enhanced bone resorption and the induction of matrix-degrading enzymes in diabetic osteoclasts. The oral administration of 10 mg/kg scopoletin elevated serum RANKL/OPG ratio and osteocalcin level reduced in db/db mice along with an increase in BMD by ~6–14%; however, it was not effective in lowering blood glucose and hemoglobin glycation. In addition, the supplementation of scopoletin elevated the formation of trabecular bones and collagen fibers in femoral epiphysis and metaphysis with a thicker epiphyseal plate and cortical bones. Furthermore, 1–20 μM scopoletin enhanced ALP activity (4.39 vs. 7.02 nmol p-nitrophenyl phosphate/min/mg protein) and deposits of mineralized bone nodules in cultured osteoblasts reduced by 33 mM glucose. The treatment of diabetic osteoblasts with scopoletin stimulated the cellular induction of BMP-2 and osteopontin and Runx2 transcription. Accordingly, the administration of scopoletin protected mice from type 2 diabetes-associated bone loss through boosting bone remodeling via the robust induction of bone turnover markers of both osteoclasts and osteoblasts. These findings suggest that scopoletin could be a potential osteoprotective agent for the treatment of diabetes-associated bone loss and fractures. MDPI 2021-06-07 /pmc/articles/PMC8227109/ /pubmed/34200167 http://dx.doi.org/10.3390/biomedicines9060648 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lee, Eun-Jung
Na, Woojin
Kang, Min-Kyung
Kim, Yun-Ho
Kim, Dong-Yeon
Oh, Hyeongjoo
Kim, Soo-Il
Oh, Su-Yeon
Park, Sohyun
Park, Kyungho
Kang, Young-Hee
Hydroxycoumarin Scopoletin Inhibits Bone Loss through Enhancing Induction of Bone Turnover Markers in a Mouse Model of Type 2 Diabetes
title Hydroxycoumarin Scopoletin Inhibits Bone Loss through Enhancing Induction of Bone Turnover Markers in a Mouse Model of Type 2 Diabetes
title_full Hydroxycoumarin Scopoletin Inhibits Bone Loss through Enhancing Induction of Bone Turnover Markers in a Mouse Model of Type 2 Diabetes
title_fullStr Hydroxycoumarin Scopoletin Inhibits Bone Loss through Enhancing Induction of Bone Turnover Markers in a Mouse Model of Type 2 Diabetes
title_full_unstemmed Hydroxycoumarin Scopoletin Inhibits Bone Loss through Enhancing Induction of Bone Turnover Markers in a Mouse Model of Type 2 Diabetes
title_short Hydroxycoumarin Scopoletin Inhibits Bone Loss through Enhancing Induction of Bone Turnover Markers in a Mouse Model of Type 2 Diabetes
title_sort hydroxycoumarin scopoletin inhibits bone loss through enhancing induction of bone turnover markers in a mouse model of type 2 diabetes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227109/
https://www.ncbi.nlm.nih.gov/pubmed/34200167
http://dx.doi.org/10.3390/biomedicines9060648
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