IgSF11-mediated phosphorylation of pyruvate kinase M2 regulates osteoclast differentiation and prevents pathological bone loss
Abstract Osteoclasts are primary bone-resorbing cells, and receptor-activated NF-kB ligand (RANKL) stimulation is the key driver of osteoclast differentiation. During late-stage differentiation, osteoclasts become multinucleated and enlarged (so-called “maturation”), suggesting their need to adapt t...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-03-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-023-00251-2 |
| _version_ | 1827984922390822912 |
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| author | Hyunsoo Kim Noriko Takegahara Yongwon Choi |
| author_facet | Hyunsoo Kim Noriko Takegahara Yongwon Choi |
| author_sort | Hyunsoo Kim |
| collection | DOAJ |
| description | Abstract Osteoclasts are primary bone-resorbing cells, and receptor-activated NF-kB ligand (RANKL) stimulation is the key driver of osteoclast differentiation. During late-stage differentiation, osteoclasts become multinucleated and enlarged (so-called “maturation”), suggesting their need to adapt to changing metabolic demands and a substantial increase in size. Here, we demonstrate that immunoglobulin superfamily 11 (IgSF11), which is required for osteoclast differentiation through an association with the postsynaptic scaffolding protein PSD-95, regulates osteoclast differentiation by controlling the activity of pyruvate kinase M isoform 2 (PKM2). By using a system that directly induces the activation of IgSF11 in a controlled manner, we identified PKM2 as a major IgSF11-induced tyrosine-phosphorylated protein. IgSF11 activates multiple Src family tyrosine kinases (SFKs), including c-Src, Fyn, and HcK, which phosphorylate PKM2 and thereby inhibit PKM2 activity. Consistently, IgSF11-deficient cells show higher PKM2 activity and defective osteoclast differentiation. Furthermore, inhibiting PKM2 activities with the specific inhibitor Shikonin rescues the impaired osteoclast differentiation in IgSF11-deficient cells, and activating PKM2 with the specific activator TEPP46 suppresses osteoclast differentiation in wild-type cells. Moreover, PKM2 activation further suppresses osteoclastic bone loss without affecting bone formation in vivo. Taken together, these results show that IgSF11 controls osteoclast differentiation through PKM2 activity, which is a metabolic switch necessary for optimal osteoclast maturation. |
| first_indexed | 2024-04-09T23:06:35Z |
| format | Article |
| id | doaj.art-ae6a28ed9b254cf8b61b181479316b00 |
| institution | Directory Open Access Journal |
| issn | 2095-6231 |
| language | English |
| last_indexed | 2024-04-09T23:06:35Z |
| publishDate | 2023-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj.art-ae6a28ed9b254cf8b61b181479316b002023-03-22T10:40:29ZengNature Publishing GroupBone Research2095-62312023-03-0111111310.1038/s41413-023-00251-2IgSF11-mediated phosphorylation of pyruvate kinase M2 regulates osteoclast differentiation and prevents pathological bone lossHyunsoo Kim0Noriko Takegahara1Yongwon Choi2Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of MedicineDepartment of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of MedicineDepartment of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of MedicineAbstract Osteoclasts are primary bone-resorbing cells, and receptor-activated NF-kB ligand (RANKL) stimulation is the key driver of osteoclast differentiation. During late-stage differentiation, osteoclasts become multinucleated and enlarged (so-called “maturation”), suggesting their need to adapt to changing metabolic demands and a substantial increase in size. Here, we demonstrate that immunoglobulin superfamily 11 (IgSF11), which is required for osteoclast differentiation through an association with the postsynaptic scaffolding protein PSD-95, regulates osteoclast differentiation by controlling the activity of pyruvate kinase M isoform 2 (PKM2). By using a system that directly induces the activation of IgSF11 in a controlled manner, we identified PKM2 as a major IgSF11-induced tyrosine-phosphorylated protein. IgSF11 activates multiple Src family tyrosine kinases (SFKs), including c-Src, Fyn, and HcK, which phosphorylate PKM2 and thereby inhibit PKM2 activity. Consistently, IgSF11-deficient cells show higher PKM2 activity and defective osteoclast differentiation. Furthermore, inhibiting PKM2 activities with the specific inhibitor Shikonin rescues the impaired osteoclast differentiation in IgSF11-deficient cells, and activating PKM2 with the specific activator TEPP46 suppresses osteoclast differentiation in wild-type cells. Moreover, PKM2 activation further suppresses osteoclastic bone loss without affecting bone formation in vivo. Taken together, these results show that IgSF11 controls osteoclast differentiation through PKM2 activity, which is a metabolic switch necessary for optimal osteoclast maturation.https://doi.org/10.1038/s41413-023-00251-2 |
| spellingShingle | Hyunsoo Kim Noriko Takegahara Yongwon Choi IgSF11-mediated phosphorylation of pyruvate kinase M2 regulates osteoclast differentiation and prevents pathological bone loss Bone Research |
| title | IgSF11-mediated phosphorylation of pyruvate kinase M2 regulates osteoclast differentiation and prevents pathological bone loss |
| title_full | IgSF11-mediated phosphorylation of pyruvate kinase M2 regulates osteoclast differentiation and prevents pathological bone loss |
| title_fullStr | IgSF11-mediated phosphorylation of pyruvate kinase M2 regulates osteoclast differentiation and prevents pathological bone loss |
| title_full_unstemmed | IgSF11-mediated phosphorylation of pyruvate kinase M2 regulates osteoclast differentiation and prevents pathological bone loss |
| title_short | IgSF11-mediated phosphorylation of pyruvate kinase M2 regulates osteoclast differentiation and prevents pathological bone loss |
| title_sort | igsf11 mediated phosphorylation of pyruvate kinase m2 regulates osteoclast differentiation and prevents pathological bone loss |
| url | https://doi.org/10.1038/s41413-023-00251-2 |
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