Spatial metabolomics reveals upregulation of several pyrophosphate-producing pathways in cortical bone of Hyp mice
Patients with the renal phosphate–wasting disease X-linked hypophosphatemia (XLH) and Hyp mice, the murine homolog of XLH, are characterized by loss-of-function mutations in phosphate-regulating endopeptidase homolog X-linked (PHEX), leading to excessive secretion of the bone-derived phosphotropic h...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-10-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.162138 |
| _version_ | 1797634366698946560 |
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| author | Achim Buck Verena M. Prade Thomas Kunzke Reinhold G. Erben Axel Walch |
| author_facet | Achim Buck Verena M. Prade Thomas Kunzke Reinhold G. Erben Axel Walch |
| author_sort | Achim Buck |
| collection | DOAJ |
| description | Patients with the renal phosphate–wasting disease X-linked hypophosphatemia (XLH) and Hyp mice, the murine homolog of XLH, are characterized by loss-of-function mutations in phosphate-regulating endopeptidase homolog X-linked (PHEX), leading to excessive secretion of the bone-derived phosphotropic hormone FGF23. The mineralization defect in patients with XLH and Hyp mice is caused by a combination of hypophosphatemia and local accumulation of mineralization-inhibiting molecules in bone. However, the mechanism by which PHEX deficiency regulates bone cell metabolism remains elusive. Here, we used spatial metabolomics by employing matrix-assisted laser desorption/ionization (MALDI) Fourier-transform ion cyclotron resonance mass spectrometry imaging (MSI) of undecalcified bone cryosections to characterize in situ metabolic changes in bones of Hyp mice in a holistic, unbiased manner. We found complex changes in Hyp bone metabolism, including perturbations in pentose phosphate, purine, pyrimidine, and phospholipid metabolism. Importantly, our study identified an upregulation of several biochemical pathways involved in intra- and extracellular production of the mineralization inhibitor pyrophosphate in the bone matrix of Hyp mice. Our data emphasize the utility of MSI–based spatial metabolomics in bone research and provide holistic in situ insights as to how Phex deficiency–induced changes in biochemical pathways in bone cells are linked to impaired bone mineralization. |
| first_indexed | 2024-03-11T12:06:41Z |
| format | Article |
| id | doaj.art-738894d08d474637a6e6f0eeaa6111fe |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:41Z |
| publishDate | 2022-10-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-738894d08d474637a6e6f0eeaa6111fe2023-11-07T16:24:43ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-10-01720Spatial metabolomics reveals upregulation of several pyrophosphate-producing pathways in cortical bone of Hyp miceAchim BuckVerena M. PradeThomas KunzkeReinhold G. ErbenAxel WalchPatients with the renal phosphate–wasting disease X-linked hypophosphatemia (XLH) and Hyp mice, the murine homolog of XLH, are characterized by loss-of-function mutations in phosphate-regulating endopeptidase homolog X-linked (PHEX), leading to excessive secretion of the bone-derived phosphotropic hormone FGF23. The mineralization defect in patients with XLH and Hyp mice is caused by a combination of hypophosphatemia and local accumulation of mineralization-inhibiting molecules in bone. However, the mechanism by which PHEX deficiency regulates bone cell metabolism remains elusive. Here, we used spatial metabolomics by employing matrix-assisted laser desorption/ionization (MALDI) Fourier-transform ion cyclotron resonance mass spectrometry imaging (MSI) of undecalcified bone cryosections to characterize in situ metabolic changes in bones of Hyp mice in a holistic, unbiased manner. We found complex changes in Hyp bone metabolism, including perturbations in pentose phosphate, purine, pyrimidine, and phospholipid metabolism. Importantly, our study identified an upregulation of several biochemical pathways involved in intra- and extracellular production of the mineralization inhibitor pyrophosphate in the bone matrix of Hyp mice. Our data emphasize the utility of MSI–based spatial metabolomics in bone research and provide holistic in situ insights as to how Phex deficiency–induced changes in biochemical pathways in bone cells are linked to impaired bone mineralization.https://doi.org/10.1172/jci.insight.162138Bone biology |
| spellingShingle | Achim Buck Verena M. Prade Thomas Kunzke Reinhold G. Erben Axel Walch Spatial metabolomics reveals upregulation of several pyrophosphate-producing pathways in cortical bone of Hyp mice JCI Insight Bone biology |
| title | Spatial metabolomics reveals upregulation of several pyrophosphate-producing pathways in cortical bone of Hyp mice |
| title_full | Spatial metabolomics reveals upregulation of several pyrophosphate-producing pathways in cortical bone of Hyp mice |
| title_fullStr | Spatial metabolomics reveals upregulation of several pyrophosphate-producing pathways in cortical bone of Hyp mice |
| title_full_unstemmed | Spatial metabolomics reveals upregulation of several pyrophosphate-producing pathways in cortical bone of Hyp mice |
| title_short | Spatial metabolomics reveals upregulation of several pyrophosphate-producing pathways in cortical bone of Hyp mice |
| title_sort | spatial metabolomics reveals upregulation of several pyrophosphate producing pathways in cortical bone of hyp mice |
| topic | Bone biology |
| url | https://doi.org/10.1172/jci.insight.162138 |
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