Loss of function mutation in Ank causes aberrant mineralization and acquisition of osteoblast-like-phenotype by the cells of the intervertebral disc
Abstract Pathological mineralization of intervertebral disc is debilitating and painful and linked to disc degeneration in a subset of human patients. An adenosine triphosphate efflux transporter, progressive ankylosis (ANK) is a regulator of extracellular inorganic pyrophosphate levels and plays an...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05893-y |
| _version_ | 1797773882270154752 |
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| author | Takashi Ohnishi Victoria Tran Kimheak Sao Pranay Ramteke William Querido Ruteja A. Barve Koen van de Wetering Makarand V. Risbud |
| author_facet | Takashi Ohnishi Victoria Tran Kimheak Sao Pranay Ramteke William Querido Ruteja A. Barve Koen van de Wetering Makarand V. Risbud |
| author_sort | Takashi Ohnishi |
| collection | DOAJ |
| description | Abstract Pathological mineralization of intervertebral disc is debilitating and painful and linked to disc degeneration in a subset of human patients. An adenosine triphosphate efflux transporter, progressive ankylosis (ANK) is a regulator of extracellular inorganic pyrophosphate levels and plays an important role in tissue mineralization. However, the function of ANK in intervertebral disc has not been fully explored. Herein we analyzed the spinal phenotype of Ank mutant mice (ank/ank) with attenuated ANK function. Micro-computed tomography and histological analysis showed that loss of ANK function results in the aberrant annulus fibrosus mineralization and peripheral disc fusions with cranial to caudal progression in the spine. Vertebrae in ank mice exhibit elevated cortical bone mass and increased tissue non-specific alkaline phosphatase-positive endplate chondrocytes with decreased subchondral endplate porosity. The acellular dystrophic mineral inclusions in the annulus fibrosus were localized adjacent to apoptotic cells and cells that acquired osteoblast-like phenotype. Fourier transform infrared spectral imaging showed that the apatite mineral in the outer annulus fibrosus had similar chemical composition to that of vertebral bone. Transcriptomic analysis of annulus fibrosus and nucleus pulposus tissues showed changes in several biological themes with a prominent dysregulation of BMAL1/CLOCK circadian regulation. The present study provides new insights into the role of ANK in the disc tissue compartments and highlights the importance of local inorganic pyrophosphate metabolism in inhibiting the mineralization of this important connective tissue. |
| first_indexed | 2024-03-12T22:12:54Z |
| format | Article |
| id | doaj.art-52af5c97e2af4fe581d193748d0a3806 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-12T22:12:54Z |
| publishDate | 2023-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-52af5c97e2af4fe581d193748d0a38062023-07-23T11:27:48ZengNature Publishing GroupCell Death and Disease2041-48892023-07-0114711610.1038/s41419-023-05893-yLoss of function mutation in Ank causes aberrant mineralization and acquisition of osteoblast-like-phenotype by the cells of the intervertebral discTakashi Ohnishi0Victoria Tran1Kimheak Sao2Pranay Ramteke3William Querido4Ruteja A. Barve5Koen van de Wetering6Makarand V. Risbud7Department of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Bioengineering, Temple UniversityDepartment of Genetics, Genome Technology Access Centre at the McDonnell Genome Institute, Washington University, School of MedicineDepartment of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine and PXE International Center of Excellence in Research and Clinical Care, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Orthopaedic Surgery, Sidney Kimmel Medical College, Thomas Jefferson UniversityAbstract Pathological mineralization of intervertebral disc is debilitating and painful and linked to disc degeneration in a subset of human patients. An adenosine triphosphate efflux transporter, progressive ankylosis (ANK) is a regulator of extracellular inorganic pyrophosphate levels and plays an important role in tissue mineralization. However, the function of ANK in intervertebral disc has not been fully explored. Herein we analyzed the spinal phenotype of Ank mutant mice (ank/ank) with attenuated ANK function. Micro-computed tomography and histological analysis showed that loss of ANK function results in the aberrant annulus fibrosus mineralization and peripheral disc fusions with cranial to caudal progression in the spine. Vertebrae in ank mice exhibit elevated cortical bone mass and increased tissue non-specific alkaline phosphatase-positive endplate chondrocytes with decreased subchondral endplate porosity. The acellular dystrophic mineral inclusions in the annulus fibrosus were localized adjacent to apoptotic cells and cells that acquired osteoblast-like phenotype. Fourier transform infrared spectral imaging showed that the apatite mineral in the outer annulus fibrosus had similar chemical composition to that of vertebral bone. Transcriptomic analysis of annulus fibrosus and nucleus pulposus tissues showed changes in several biological themes with a prominent dysregulation of BMAL1/CLOCK circadian regulation. The present study provides new insights into the role of ANK in the disc tissue compartments and highlights the importance of local inorganic pyrophosphate metabolism in inhibiting the mineralization of this important connective tissue.https://doi.org/10.1038/s41419-023-05893-y |
| spellingShingle | Takashi Ohnishi Victoria Tran Kimheak Sao Pranay Ramteke William Querido Ruteja A. Barve Koen van de Wetering Makarand V. Risbud Loss of function mutation in Ank causes aberrant mineralization and acquisition of osteoblast-like-phenotype by the cells of the intervertebral disc Cell Death and Disease |
| title | Loss of function mutation in Ank causes aberrant mineralization and acquisition of osteoblast-like-phenotype by the cells of the intervertebral disc |
| title_full | Loss of function mutation in Ank causes aberrant mineralization and acquisition of osteoblast-like-phenotype by the cells of the intervertebral disc |
| title_fullStr | Loss of function mutation in Ank causes aberrant mineralization and acquisition of osteoblast-like-phenotype by the cells of the intervertebral disc |
| title_full_unstemmed | Loss of function mutation in Ank causes aberrant mineralization and acquisition of osteoblast-like-phenotype by the cells of the intervertebral disc |
| title_short | Loss of function mutation in Ank causes aberrant mineralization and acquisition of osteoblast-like-phenotype by the cells of the intervertebral disc |
| title_sort | loss of function mutation in ank causes aberrant mineralization and acquisition of osteoblast like phenotype by the cells of the intervertebral disc |
| url | https://doi.org/10.1038/s41419-023-05893-y |
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