Targeted conditional collagen XII deletion alters tendon function
Collagen XII is a fibril-associated collagen with interrupted triple helices (FACIT). This non-fibrillar collagen is a homotrimer composed of three α1(XII) chains assembled into a collagenous molecule with a C terminal collagenous domain and a large N terminal non-collagenous domain. During tendon d...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Matrix Biology Plus |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590028522000230 |
| _version_ | 1797978794804379648 |
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| author | Ashley Fung Mei Sun Louis J. Soslowsky David E. Birk |
| author_facet | Ashley Fung Mei Sun Louis J. Soslowsky David E. Birk |
| author_sort | Ashley Fung |
| collection | DOAJ |
| description | Collagen XII is a fibril-associated collagen with interrupted triple helices (FACIT). This non-fibrillar collagen is a homotrimer composed of three α1(XII) chains assembled into a collagenous molecule with a C terminal collagenous domain and a large N terminal non-collagenous domain. During tendon development and growth, collagen XII is broadly expressed throughout the extracellular matrix and enriched pericellularly around tenocytes. Tendons in a global Col12a1-/- knockout model demonstrated disrupted fibril and fiber structure and disordered tenocyte organization, highlighting the critical regulatory roles of collagen XII in determining tendon structure and function. However, muscle and bone also are affected in the collagen XII knockout model. Therefore, secondary effects on tendon due to involvement of bone and muscle may occur in the global knockout. The global knockout does not allow the definition of intrinsic mechanisms involving collagen XII in tendon versus extrinsic roles involving muscle and bone. To address this limitation, we created and characterized a conditional Col12a1-null mouse model to permit the spatial and temporal manipulation of Col12a1 expression. Collagen XII knockout was targeted to tendons by breeding conditional Col12a1flox/flox mice with Scleraxis-Cre (Scx-Cre) mice to yield a tendon-specific Col12a1-null mouse line, Col12a1Δten/Δten. Both mRNA and protein expression in Col12a1Δten/Δten mice decreased to near baseline levels in flexor digitorum longus tendons (FDL). Collagen XII immuno-localization revealed an absence of reactivity in the tendon proper, but there was reactivity in the cells of the surrounding peritenon. This supports a targeted knockout in tenocytes while peritenon cells from a non-tendon lineage were not targeted and retained collagen XII expression. The tendon-targeted, Col12a1Δten/Δten mice had significantly reduced forelimb grip strength, altered gait and a significant decrease in biomechanical properties. While the observed decrease in tendon modulus suggests that differences in tendon material properties in the absence of Col12a1 expression underlie the functional deficiencies. Together, these findings suggest an intrinsic role for collagen XII critical for development of a functional tendon. |
| first_indexed | 2024-04-11T05:28:42Z |
| format | Article |
| id | doaj.art-ddd609a90dc6404d9795319deeef9cba |
| institution | Directory Open Access Journal |
| issn | 2590-0285 |
| language | English |
| last_indexed | 2024-04-11T05:28:42Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Matrix Biology Plus |
| spelling | doaj.art-ddd609a90dc6404d9795319deeef9cba2022-12-23T04:41:56ZengElsevierMatrix Biology Plus2590-02852022-12-0116100123Targeted conditional collagen XII deletion alters tendon functionAshley Fung0Mei Sun1Louis J. Soslowsky2David E. Birk3McKay Orthopedic Research Laboratory, University of Pennsylvania, Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104, USADepartment of Molecular Pharmacology & Physiology, University of South Florida, Morsani College of Medicine, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, USAMcKay Orthopedic Research Laboratory, University of Pennsylvania, Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104, USAMcKay Orthopedic Research Laboratory, University of Pennsylvania, Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104, USA; Department of Molecular Pharmacology & Physiology, University of South Florida, Morsani College of Medicine, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, USA; Corresponding author at: Department of Molecular Pharmacology & Physiology, University of South Florida, Morsani College of Medicine, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, USA.Collagen XII is a fibril-associated collagen with interrupted triple helices (FACIT). This non-fibrillar collagen is a homotrimer composed of three α1(XII) chains assembled into a collagenous molecule with a C terminal collagenous domain and a large N terminal non-collagenous domain. During tendon development and growth, collagen XII is broadly expressed throughout the extracellular matrix and enriched pericellularly around tenocytes. Tendons in a global Col12a1-/- knockout model demonstrated disrupted fibril and fiber structure and disordered tenocyte organization, highlighting the critical regulatory roles of collagen XII in determining tendon structure and function. However, muscle and bone also are affected in the collagen XII knockout model. Therefore, secondary effects on tendon due to involvement of bone and muscle may occur in the global knockout. The global knockout does not allow the definition of intrinsic mechanisms involving collagen XII in tendon versus extrinsic roles involving muscle and bone. To address this limitation, we created and characterized a conditional Col12a1-null mouse model to permit the spatial and temporal manipulation of Col12a1 expression. Collagen XII knockout was targeted to tendons by breeding conditional Col12a1flox/flox mice with Scleraxis-Cre (Scx-Cre) mice to yield a tendon-specific Col12a1-null mouse line, Col12a1Δten/Δten. Both mRNA and protein expression in Col12a1Δten/Δten mice decreased to near baseline levels in flexor digitorum longus tendons (FDL). Collagen XII immuno-localization revealed an absence of reactivity in the tendon proper, but there was reactivity in the cells of the surrounding peritenon. This supports a targeted knockout in tenocytes while peritenon cells from a non-tendon lineage were not targeted and retained collagen XII expression. The tendon-targeted, Col12a1Δten/Δten mice had significantly reduced forelimb grip strength, altered gait and a significant decrease in biomechanical properties. While the observed decrease in tendon modulus suggests that differences in tendon material properties in the absence of Col12a1 expression underlie the functional deficiencies. Together, these findings suggest an intrinsic role for collagen XII critical for development of a functional tendon.http://www.sciencedirect.com/science/article/pii/S2590028522000230Collagen XIIConditional mouse modelTendonTransgenicCol12a1Biomechanics |
| spellingShingle | Ashley Fung Mei Sun Louis J. Soslowsky David E. Birk Targeted conditional collagen XII deletion alters tendon function Matrix Biology Plus Collagen XII Conditional mouse model Tendon Transgenic Col12a1 Biomechanics |
| title | Targeted conditional collagen XII deletion alters tendon function |
| title_full | Targeted conditional collagen XII deletion alters tendon function |
| title_fullStr | Targeted conditional collagen XII deletion alters tendon function |
| title_full_unstemmed | Targeted conditional collagen XII deletion alters tendon function |
| title_short | Targeted conditional collagen XII deletion alters tendon function |
| title_sort | targeted conditional collagen xii deletion alters tendon function |
| topic | Collagen XII Conditional mouse model Tendon Transgenic Col12a1 Biomechanics |
| url | http://www.sciencedirect.com/science/article/pii/S2590028522000230 |
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