The microbial metabolite imidazole propionate dysregulates bone homeostasis by inhibiting AMP-activated protein kinase (AMPK) signaling
Abstract Microbial metabolites provide numerous benefits to the human body but can also contribute to diseases such as obesity, diabetes, cancer, and bone disorders. However, the role of imidazole propionate (ImP), a histidine-derived metabolite produced by the intestinal microbiome, in bone metabol...
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Nature Portfolio
2024-12-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-07316-w |
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| author | Suk-Gyun Park Jung-Woo Kim Ju Han Song Seung-Hee Kwon Sin-Hye Oh Xianyu Piao Zhao Wang Je-Hwang Ryu Nacksung Kim Ok-Su Kim Jeong-Tae Koh |
| author_facet | Suk-Gyun Park Jung-Woo Kim Ju Han Song Seung-Hee Kwon Sin-Hye Oh Xianyu Piao Zhao Wang Je-Hwang Ryu Nacksung Kim Ok-Su Kim Jeong-Tae Koh |
| author_sort | Suk-Gyun Park |
| collection | DOAJ |
| description | Abstract Microbial metabolites provide numerous benefits to the human body but can also contribute to diseases such as obesity, diabetes, cancer, and bone disorders. However, the role of imidazole propionate (ImP), a histidine-derived metabolite produced by the intestinal microbiome, in bone metabolism and the development of osteoporosis is still poorly understood. In this study, we investigated the role of ImP and its underlying mechanisms in regulating bone homeostasis. When ImP was administered to 8-week-old mice for 4 weeks, bone loss was observed, along with a decrease in alkaline phosphatase-positive osteoblast cells. Additionally, bone marrow stromal cells (BMSCs) isolated from ImP-treated mice exhibited reduced osteogenic potential. In BMSCs from control mice, ImP treatment inhibited BMP2-induced osteoblast differentiation while promoting adipocyte differentiation. However, ImP had no effect on RANKL-induced osteoclast differentiation or activity in bone marrow macrophages. Mechanistically, ImP treatment increased p38γ phosphorylation and decreased AMPK (T172) phosphorylation in BMSCs. Suppression of p38γ expression using si-p38γ reversed the inhibitory effects of ImP on osteoblast differentiation, with a concurrent increase in AMPK (T172) phosphorylation. Conversely, ImP stimulated adipocyte differentiation by decreasing AMPK (T172) phosphorylation. Treatment with the AMPK agonist metformin significantly reversed the inhibitory effects of ImP on osteoblast differentiation and the promotion of adipocyte differentiation, along with enhanced AMPK (T172) phosphorylation. These findings suggest that the microbial metabolite ImP may disrupt bone homeostasis by stimulating p38γ phosphorylation and inhibiting the AMPK pathway, presenting a potential therapeutic target for managing metabolic bone diseases. |
| format | Article |
| id | doaj-art-da4cf9d172044fa2aa9bdee70dbd4e89 |
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| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
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| series | Communications Biology |
| spelling | doaj-art-da4cf9d172044fa2aa9bdee70dbd4e892025-08-20T02:31:55ZengNature PortfolioCommunications Biology2399-36422024-12-017111210.1038/s42003-024-07316-wThe microbial metabolite imidazole propionate dysregulates bone homeostasis by inhibiting AMP-activated protein kinase (AMPK) signalingSuk-Gyun Park0Jung-Woo Kim1Ju Han Song2Seung-Hee Kwon3Sin-Hye Oh4Xianyu Piao5Zhao Wang6Je-Hwang Ryu7Nacksung Kim8Ok-Su Kim9Jeong-Tae Koh10Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National UniversityDepartment of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National UniversityDepartment of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National UniversityDepartment of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National UniversityDepartment of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National UniversityDepartment of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National UniversityDepartment of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National UniversityDepartment of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National UniversityHard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National UniversityHard-Tissue Biointerface Research Center, School of Dentistry, Chonnam National UniversityDepartment of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National UniversityAbstract Microbial metabolites provide numerous benefits to the human body but can also contribute to diseases such as obesity, diabetes, cancer, and bone disorders. However, the role of imidazole propionate (ImP), a histidine-derived metabolite produced by the intestinal microbiome, in bone metabolism and the development of osteoporosis is still poorly understood. In this study, we investigated the role of ImP and its underlying mechanisms in regulating bone homeostasis. When ImP was administered to 8-week-old mice for 4 weeks, bone loss was observed, along with a decrease in alkaline phosphatase-positive osteoblast cells. Additionally, bone marrow stromal cells (BMSCs) isolated from ImP-treated mice exhibited reduced osteogenic potential. In BMSCs from control mice, ImP treatment inhibited BMP2-induced osteoblast differentiation while promoting adipocyte differentiation. However, ImP had no effect on RANKL-induced osteoclast differentiation or activity in bone marrow macrophages. Mechanistically, ImP treatment increased p38γ phosphorylation and decreased AMPK (T172) phosphorylation in BMSCs. Suppression of p38γ expression using si-p38γ reversed the inhibitory effects of ImP on osteoblast differentiation, with a concurrent increase in AMPK (T172) phosphorylation. Conversely, ImP stimulated adipocyte differentiation by decreasing AMPK (T172) phosphorylation. Treatment with the AMPK agonist metformin significantly reversed the inhibitory effects of ImP on osteoblast differentiation and the promotion of adipocyte differentiation, along with enhanced AMPK (T172) phosphorylation. These findings suggest that the microbial metabolite ImP may disrupt bone homeostasis by stimulating p38γ phosphorylation and inhibiting the AMPK pathway, presenting a potential therapeutic target for managing metabolic bone diseases.https://doi.org/10.1038/s42003-024-07316-w |
| spellingShingle | Suk-Gyun Park Jung-Woo Kim Ju Han Song Seung-Hee Kwon Sin-Hye Oh Xianyu Piao Zhao Wang Je-Hwang Ryu Nacksung Kim Ok-Su Kim Jeong-Tae Koh The microbial metabolite imidazole propionate dysregulates bone homeostasis by inhibiting AMP-activated protein kinase (AMPK) signaling Communications Biology |
| title | The microbial metabolite imidazole propionate dysregulates bone homeostasis by inhibiting AMP-activated protein kinase (AMPK) signaling |
| title_full | The microbial metabolite imidazole propionate dysregulates bone homeostasis by inhibiting AMP-activated protein kinase (AMPK) signaling |
| title_fullStr | The microbial metabolite imidazole propionate dysregulates bone homeostasis by inhibiting AMP-activated protein kinase (AMPK) signaling |
| title_full_unstemmed | The microbial metabolite imidazole propionate dysregulates bone homeostasis by inhibiting AMP-activated protein kinase (AMPK) signaling |
| title_short | The microbial metabolite imidazole propionate dysregulates bone homeostasis by inhibiting AMP-activated protein kinase (AMPK) signaling |
| title_sort | microbial metabolite imidazole propionate dysregulates bone homeostasis by inhibiting amp activated protein kinase ampk signaling |
| url | https://doi.org/10.1038/s42003-024-07316-w |
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