Downregulation of the Autism Spectrum Disorder Gene Shank2 Decreases Bone Mass in Male Mice
ABSTRACT Mutations of the postsynaptic scaffold protein Shank2 lead to autism spectrum disorders (ASD). These patients frequently suffer from higher fracture risk. Here, we investigated whether Shank2 directly regulates bone mass. We show that Shank2 is expressed in bone and that Shank2 levels are i...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-02-01
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| Series: | JBMR Plus |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jbm4.10711 |
| _version_ | 1797935171112009728 |
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| author | Mubashir Ahmad Nadine Stirmlinger Irfana Jan Ulrich Stifel Sooyeon Lee Marcel Weingandt Ulrike Kelp Jürgen Bockmann Anita Ignatius Tobias M. Böckers Jan Tuckermann |
| author_facet | Mubashir Ahmad Nadine Stirmlinger Irfana Jan Ulrich Stifel Sooyeon Lee Marcel Weingandt Ulrike Kelp Jürgen Bockmann Anita Ignatius Tobias M. Böckers Jan Tuckermann |
| author_sort | Mubashir Ahmad |
| collection | DOAJ |
| description | ABSTRACT Mutations of the postsynaptic scaffold protein Shank2 lead to autism spectrum disorders (ASD). These patients frequently suffer from higher fracture risk. Here, we investigated whether Shank2 directly regulates bone mass. We show that Shank2 is expressed in bone and that Shank2 levels are increased during osteoblastogenesis. Knockdown of Shank2 by siRNA targeting the encoding regions for PDZ and SAM domain inhibits osteoblastogenesis of primary murine calvarial osteoblasts. Shank2 knockout mice (Shank2−/−) have a decreased bone mass due to reduced osteoblastogenesis and bone formation, whereas bone resorption remains unaffected. Induced pluripotent stem cells (iPSCs)‐derived osteoblasts from a loss‐of‐function Shank2 mutation in a patient showed a significantly reduced osteoblast differentiation potential. Moreover, silencing of known Shank2 interacting proteins revealed that a majority of them promote osteoblast differentiation. From this we conclude that Shank2 and interacting proteins known from the central nervous system are decisive regulators in osteoblast differentiation. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. |
| first_indexed | 2024-04-10T18:11:18Z |
| format | Article |
| id | doaj.art-46146bcba9f2479d9d2e4235043799ce |
| institution | Directory Open Access Journal |
| issn | 2473-4039 |
| language | English |
| last_indexed | 2024-04-10T18:11:18Z |
| publishDate | 2023-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | JBMR Plus |
| spelling | doaj.art-46146bcba9f2479d9d2e4235043799ce2023-02-02T10:56:20ZengWileyJBMR Plus2473-40392023-02-0172n/an/a10.1002/jbm4.10711Downregulation of the Autism Spectrum Disorder Gene Shank2 Decreases Bone Mass in Male MiceMubashir Ahmad0Nadine Stirmlinger1Irfana Jan2Ulrich Stifel3Sooyeon Lee4Marcel Weingandt5Ulrike Kelp6Jürgen Bockmann7Anita Ignatius8Tobias M. Böckers9Jan Tuckermann10Institute of Comparative Molecular Endocrinology (CME) Ulm University Ulm GermanyInstitute for Anatomy and Cell Biology Ulm University Ulm GermanyInstitute of Comparative Molecular Endocrinology (CME) Ulm University Ulm GermanyInstitute of Comparative Molecular Endocrinology (CME) Ulm University Ulm GermanyInstitute of Comparative Molecular Endocrinology (CME) Ulm University Ulm GermanyInstitute of Comparative Molecular Endocrinology (CME) Ulm University Ulm GermanyInstitute of Comparative Molecular Endocrinology (CME) Ulm University Ulm GermanyInstitute for Anatomy and Cell Biology Ulm University Ulm GermanyInstitute of Orthopaedic Research and Biomechanics Ulm University Ulm GermanyInstitute for Anatomy and Cell Biology Ulm University Ulm GermanyInstitute of Comparative Molecular Endocrinology (CME) Ulm University Ulm GermanyABSTRACT Mutations of the postsynaptic scaffold protein Shank2 lead to autism spectrum disorders (ASD). These patients frequently suffer from higher fracture risk. Here, we investigated whether Shank2 directly regulates bone mass. We show that Shank2 is expressed in bone and that Shank2 levels are increased during osteoblastogenesis. Knockdown of Shank2 by siRNA targeting the encoding regions for PDZ and SAM domain inhibits osteoblastogenesis of primary murine calvarial osteoblasts. Shank2 knockout mice (Shank2−/−) have a decreased bone mass due to reduced osteoblastogenesis and bone formation, whereas bone resorption remains unaffected. Induced pluripotent stem cells (iPSCs)‐derived osteoblasts from a loss‐of‐function Shank2 mutation in a patient showed a significantly reduced osteoblast differentiation potential. Moreover, silencing of known Shank2 interacting proteins revealed that a majority of them promote osteoblast differentiation. From this we conclude that Shank2 and interacting proteins known from the central nervous system are decisive regulators in osteoblast differentiation. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.https://doi.org/10.1002/jbm4.10711BONE MASSOSTEOBLAST DIFFERENTIATIONSHANK2 |
| spellingShingle | Mubashir Ahmad Nadine Stirmlinger Irfana Jan Ulrich Stifel Sooyeon Lee Marcel Weingandt Ulrike Kelp Jürgen Bockmann Anita Ignatius Tobias M. Böckers Jan Tuckermann Downregulation of the Autism Spectrum Disorder Gene Shank2 Decreases Bone Mass in Male Mice JBMR Plus BONE MASS OSTEOBLAST DIFFERENTIATION SHANK2 |
| title | Downregulation of the Autism Spectrum Disorder Gene Shank2 Decreases Bone Mass in Male Mice |
| title_full | Downregulation of the Autism Spectrum Disorder Gene Shank2 Decreases Bone Mass in Male Mice |
| title_fullStr | Downregulation of the Autism Spectrum Disorder Gene Shank2 Decreases Bone Mass in Male Mice |
| title_full_unstemmed | Downregulation of the Autism Spectrum Disorder Gene Shank2 Decreases Bone Mass in Male Mice |
| title_short | Downregulation of the Autism Spectrum Disorder Gene Shank2 Decreases Bone Mass in Male Mice |
| title_sort | downregulation of the autism spectrum disorder gene shank2 decreases bone mass in male mice |
| topic | BONE MASS OSTEOBLAST DIFFERENTIATION SHANK2 |
| url | https://doi.org/10.1002/jbm4.10711 |
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