Cross-species comparisons reveal resistance of human skeletal stem cells to inhibition by non-steroidal anti-inflammatory drugs
Fracture healing is highly dependent on an early inflammatory response in which prostaglandin production by cyclo-oxygenases (COX) plays a crucial role. Current patient analgesia regimens favor opioids over Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) since the latter have been implicated in delay...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Endocrinology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2022.924927/full |
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| author | L. Henry Goodnough Thomas H. Ambrosi Thomas H. Ambrosi Holly M. Steininger M. Gohazrua K. Butler Malachia Y. Hoover HyeRan Choo Noelle L. Van Rysselberghe Michael J. Bellino Julius A. Bishop Michael J. Gardner Charles K. F. Chan Charles K. F. Chan |
| author_facet | L. Henry Goodnough Thomas H. Ambrosi Thomas H. Ambrosi Holly M. Steininger M. Gohazrua K. Butler Malachia Y. Hoover HyeRan Choo Noelle L. Van Rysselberghe Michael J. Bellino Julius A. Bishop Michael J. Gardner Charles K. F. Chan Charles K. F. Chan |
| author_sort | L. Henry Goodnough |
| collection | DOAJ |
| description | Fracture healing is highly dependent on an early inflammatory response in which prostaglandin production by cyclo-oxygenases (COX) plays a crucial role. Current patient analgesia regimens favor opioids over Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) since the latter have been implicated in delayed fracture healing. While animal studies broadly support a deleterious role of NSAID treatment to bone-regenerative processes, data for human fracture healing remains contradictory. In this study, we prospectively isolated mouse and human skeletal stem cells (SSCs) from fractures and compared the effect of various NSAIDs on their function. We found that osteochondrogenic differentiation of COX2-expressing mouse SSCs was impaired by NSAID treatment. In contrast, human SSCs (hSSC) downregulated COX2 expression during differentiation and showed impaired osteogenic capacity if COX2 was lentivirally overexpressed. Accordingly, short- and long-term treatment of hSSCs with non-selective and selective COX2 inhibitors did not affect colony forming ability, chondrogenic, and osteogenic differentiation potential in vitro. When hSSCs were transplanted ectopically into NSG mice treated with Indomethacin, graft mineralization was unaltered compared to vehicle injected mice. Thus, our results might contribute to understanding species-specific differences in NSAID sensitivity during fracture healing and support emerging clinical data which conflicts with other earlier observations that NSAID administration for post-operative analgesia for treatment of bone fractures are unsafe for patients. |
| first_indexed | 2024-04-11T14:19:28Z |
| format | Article |
| id | doaj.art-d28ce38554054fc2a39b4c9b32bde2c2 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-11T14:19:28Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-d28ce38554054fc2a39b4c9b32bde2c22022-12-22T04:19:07ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-08-011310.3389/fendo.2022.924927924927Cross-species comparisons reveal resistance of human skeletal stem cells to inhibition by non-steroidal anti-inflammatory drugsL. Henry Goodnough0Thomas H. Ambrosi1Thomas H. Ambrosi2Holly M. Steininger3M. Gohazrua K. Butler4Malachia Y. Hoover5HyeRan Choo6Noelle L. Van Rysselberghe7Michael J. Bellino8Julius A. Bishop9Michael J. Gardner10Charles K. F. Chan11Charles K. F. Chan12Department of Orthopaedic Surgery, Stanford Hospitals and Clinics, Stanford, CA, United StatesInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United StatesDivision of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, United StatesInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United StatesInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United StatesInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United StatesDivision of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, United StatesDepartment of Orthopaedic Surgery, Stanford Hospitals and Clinics, Stanford, CA, United StatesDepartment of Orthopaedic Surgery, Stanford Hospitals and Clinics, Stanford, CA, United StatesDepartment of Orthopaedic Surgery, Stanford Hospitals and Clinics, Stanford, CA, United StatesDepartment of Orthopaedic Surgery, Stanford Hospitals and Clinics, Stanford, CA, United StatesInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United StatesDivision of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, United StatesFracture healing is highly dependent on an early inflammatory response in which prostaglandin production by cyclo-oxygenases (COX) plays a crucial role. Current patient analgesia regimens favor opioids over Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) since the latter have been implicated in delayed fracture healing. While animal studies broadly support a deleterious role of NSAID treatment to bone-regenerative processes, data for human fracture healing remains contradictory. In this study, we prospectively isolated mouse and human skeletal stem cells (SSCs) from fractures and compared the effect of various NSAIDs on their function. We found that osteochondrogenic differentiation of COX2-expressing mouse SSCs was impaired by NSAID treatment. In contrast, human SSCs (hSSC) downregulated COX2 expression during differentiation and showed impaired osteogenic capacity if COX2 was lentivirally overexpressed. Accordingly, short- and long-term treatment of hSSCs with non-selective and selective COX2 inhibitors did not affect colony forming ability, chondrogenic, and osteogenic differentiation potential in vitro. When hSSCs were transplanted ectopically into NSG mice treated with Indomethacin, graft mineralization was unaltered compared to vehicle injected mice. Thus, our results might contribute to understanding species-specific differences in NSAID sensitivity during fracture healing and support emerging clinical data which conflicts with other earlier observations that NSAID administration for post-operative analgesia for treatment of bone fractures are unsafe for patients.https://www.frontiersin.org/articles/10.3389/fendo.2022.924927/fullskeletal stem cells (SSCs)non-steroid antiinflamatory drugsspecies specificitybone regenerationinflammationfracture healing |
| spellingShingle | L. Henry Goodnough Thomas H. Ambrosi Thomas H. Ambrosi Holly M. Steininger M. Gohazrua K. Butler Malachia Y. Hoover HyeRan Choo Noelle L. Van Rysselberghe Michael J. Bellino Julius A. Bishop Michael J. Gardner Charles K. F. Chan Charles K. F. Chan Cross-species comparisons reveal resistance of human skeletal stem cells to inhibition by non-steroidal anti-inflammatory drugs Frontiers in Endocrinology skeletal stem cells (SSCs) non-steroid antiinflamatory drugs species specificity bone regeneration inflammation fracture healing |
| title | Cross-species comparisons reveal resistance of human skeletal stem cells to inhibition by non-steroidal anti-inflammatory drugs |
| title_full | Cross-species comparisons reveal resistance of human skeletal stem cells to inhibition by non-steroidal anti-inflammatory drugs |
| title_fullStr | Cross-species comparisons reveal resistance of human skeletal stem cells to inhibition by non-steroidal anti-inflammatory drugs |
| title_full_unstemmed | Cross-species comparisons reveal resistance of human skeletal stem cells to inhibition by non-steroidal anti-inflammatory drugs |
| title_short | Cross-species comparisons reveal resistance of human skeletal stem cells to inhibition by non-steroidal anti-inflammatory drugs |
| title_sort | cross species comparisons reveal resistance of human skeletal stem cells to inhibition by non steroidal anti inflammatory drugs |
| topic | skeletal stem cells (SSCs) non-steroid antiinflamatory drugs species specificity bone regeneration inflammation fracture healing |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.924927/full |
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