Impaired fracture healing is associated with callus chondro-osseous junction abnormalities in periostin-null and osteopontin-null mice
Periostin and osteopontin are matricellular proteins abundantly expressed in bone fracture callus. Null mutation of either the periostin (Postn) gene or the osteopontin (Spp1) gene can impair bone fracture healing. However, the cell and molecular pathways affected by loss of POSTN or SPP1 which lead...
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Frontiers Media S.A.
2025-01-01
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| Series: | Experimental Biology and Medicine |
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| Online Access: | https://www.ebm-journal.org/articles/10.3389/ebm.2024.10066/full |
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| author | Marc Teitelbaum Marc Teitelbaum Maya D. Culbertson Charlene Wetterstrand J. Patrick O’Connor J. Patrick O’Connor |
| author_facet | Marc Teitelbaum Marc Teitelbaum Maya D. Culbertson Charlene Wetterstrand J. Patrick O’Connor J. Patrick O’Connor |
| author_sort | Marc Teitelbaum |
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| description | Periostin and osteopontin are matricellular proteins abundantly expressed in bone fracture callus. Null mutation of either the periostin (Postn) gene or the osteopontin (Spp1) gene can impair bone fracture healing. However, the cell and molecular pathways affected by loss of POSTN or SPP1 which lead to impaired fracture healing are not well understood. To identify potential pathways, a detailed radiological, histological, and immunohistochemical analysis of femur fracture healing in Postn-null (PostnKO), Spp1-null (Spp1KO), and normal (WT) mice was performed. Apparent changes in specific protein levels identified by immunohistochemistry were confirmed by mRNA quantitation. Comparisons between the PostnKO and Spp1KO fracture calluses were confounded by interactions between the two genes; loss of Postn reduced Spp1 expression and loss of Spp1 reduced Postn expression. Consequently, alterations in fracture healing between mice heterozygous for the Postn-null allele (PostnHET) as well as the PostnKO and Spp1KO mice were similar. Calluses from PostnHET, PostnKO, and Spp1KO mice all had dysmorphic chondro-osseous junctions and reduced numbers of osteoclasts. The dysmorphic chondro-osseous junctions in the PostnHET, PostnKO, and Spp1KO calluses were associated with reduced numbers of MMP-13 expressing hypertrophic chondrocytes, consistent with delayed cartilage resolution. Unlike collagen X expressing callus chondrocytes, chondrocytes only expressed MMP-13 when localized to the chondro-osseous junction or after traversing the chondro-osseous junction. Cyclooxygenase-2 (COX-2) expression also appeared to be reduced in osteoclasts from the PostnHET, PostnKO, and Spp1KO calluses, including in those osteoclasts localized at the chondro-osseous junction. The results indicate that POSTN and SPP1 are necessary for normal chondro-osseous junction formation and that signaling from the chondro-osseous junction, possibly from COX-2 expressing osteoclasts, regulates callus vasculogenesis and chondrocyte hypertrophy necessary for endochondral ossification during fracture healing. |
| format | Article |
| id | doaj-art-becde497812948f3b94f701008cfeea7 |
| institution | Kabale University |
| issn | 1535-3699 |
| language | English |
| publishDate | 2025-01-01 |
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| series | Experimental Biology and Medicine |
| spelling | doaj-art-becde497812948f3b94f701008cfeea72025-01-22T04:11:24ZengFrontiers Media S.A.Experimental Biology and Medicine1535-36992025-01-0124910.3389/ebm.2024.1006610066Impaired fracture healing is associated with callus chondro-osseous junction abnormalities in periostin-null and osteopontin-null miceMarc Teitelbaum0Marc Teitelbaum1Maya D. Culbertson2Charlene Wetterstrand3J. Patrick O’Connor4J. Patrick O’Connor5Department of Orthopaedics, Rutgers-New Jersey Medical School, Newark, NJ, United StatesRutgers-School of Graduate Studies, Newark Health Sciences Campus, Newark, NJ, United StatesDepartment of Orthopaedics, Rutgers-New Jersey Medical School, Newark, NJ, United StatesDepartment of Orthopaedics, Rutgers-New Jersey Medical School, Newark, NJ, United StatesDepartment of Orthopaedics, Rutgers-New Jersey Medical School, Newark, NJ, United StatesRutgers-School of Graduate Studies, Newark Health Sciences Campus, Newark, NJ, United StatesPeriostin and osteopontin are matricellular proteins abundantly expressed in bone fracture callus. Null mutation of either the periostin (Postn) gene or the osteopontin (Spp1) gene can impair bone fracture healing. However, the cell and molecular pathways affected by loss of POSTN or SPP1 which lead to impaired fracture healing are not well understood. To identify potential pathways, a detailed radiological, histological, and immunohistochemical analysis of femur fracture healing in Postn-null (PostnKO), Spp1-null (Spp1KO), and normal (WT) mice was performed. Apparent changes in specific protein levels identified by immunohistochemistry were confirmed by mRNA quantitation. Comparisons between the PostnKO and Spp1KO fracture calluses were confounded by interactions between the two genes; loss of Postn reduced Spp1 expression and loss of Spp1 reduced Postn expression. Consequently, alterations in fracture healing between mice heterozygous for the Postn-null allele (PostnHET) as well as the PostnKO and Spp1KO mice were similar. Calluses from PostnHET, PostnKO, and Spp1KO mice all had dysmorphic chondro-osseous junctions and reduced numbers of osteoclasts. The dysmorphic chondro-osseous junctions in the PostnHET, PostnKO, and Spp1KO calluses were associated with reduced numbers of MMP-13 expressing hypertrophic chondrocytes, consistent with delayed cartilage resolution. Unlike collagen X expressing callus chondrocytes, chondrocytes only expressed MMP-13 when localized to the chondro-osseous junction or after traversing the chondro-osseous junction. Cyclooxygenase-2 (COX-2) expression also appeared to be reduced in osteoclasts from the PostnHET, PostnKO, and Spp1KO calluses, including in those osteoclasts localized at the chondro-osseous junction. The results indicate that POSTN and SPP1 are necessary for normal chondro-osseous junction formation and that signaling from the chondro-osseous junction, possibly from COX-2 expressing osteoclasts, regulates callus vasculogenesis and chondrocyte hypertrophy necessary for endochondral ossification during fracture healing.https://www.ebm-journal.org/articles/10.3389/ebm.2024.10066/fullperiostinosteopontinendochondral ossificationchondro-osseous junctionfracture healingosteoclast |
| spellingShingle | Marc Teitelbaum Marc Teitelbaum Maya D. Culbertson Charlene Wetterstrand J. Patrick O’Connor J. Patrick O’Connor Impaired fracture healing is associated with callus chondro-osseous junction abnormalities in periostin-null and osteopontin-null mice Experimental Biology and Medicine periostin osteopontin endochondral ossification chondro-osseous junction fracture healing osteoclast |
| title | Impaired fracture healing is associated with callus chondro-osseous junction abnormalities in periostin-null and osteopontin-null mice |
| title_full | Impaired fracture healing is associated with callus chondro-osseous junction abnormalities in periostin-null and osteopontin-null mice |
| title_fullStr | Impaired fracture healing is associated with callus chondro-osseous junction abnormalities in periostin-null and osteopontin-null mice |
| title_full_unstemmed | Impaired fracture healing is associated with callus chondro-osseous junction abnormalities in periostin-null and osteopontin-null mice |
| title_short | Impaired fracture healing is associated with callus chondro-osseous junction abnormalities in periostin-null and osteopontin-null mice |
| title_sort | impaired fracture healing is associated with callus chondro osseous junction abnormalities in periostin null and osteopontin null mice |
| topic | periostin osteopontin endochondral ossification chondro-osseous junction fracture healing osteoclast |
| url | https://www.ebm-journal.org/articles/10.3389/ebm.2024.10066/full |
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