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p38 MAPK signaling in postnatal tendon growth and remodeling.

Schwartz AJ, Sarver DC, Sugg KB, Dzierzawski JT, Gumucio JP, Mendias CL - PLoS ONE (2015)

Bottom Line: By 28 days after overload, tendon mass had increased by 30% compared to non-overloaded samples, and cross-sectional area (CSA) increased by around 50%, with most of the change occurring in the neotendon.Inhibition of p38 MAPK resulted in a profound decrease in IL6 expression, and had a modest effect on the expression of other ECM and cell proliferation genes, but had a negligible impact on overall tendon growth.The combined results from this study provided novel insights into tendon mechanobiology, and suggest that p38 MAPK signaling does not appear to be necessary for tendon growth in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.

ABSTRACT
Tendon is a dynamic tissue whose structure and function is influenced by mechanical loading, but little is known about the fundamental mechanisms that regulate tendon growth and remodeling in vivo. Data from cultured tendon fibroblasts indicated that the p38 MAPK pathway plays an important role in tendon fibroblast proliferation and collagen synthesis in vitro. To gain greater insight into the mechanisms of tendon growth, and explore the role of p38 MAPK signaling in this process, we tested the hypotheses that inducing plantaris tendon growth through the ablation of the synergist Achilles tendon would result in rapid expansion of a neotendon matrix surrounding the original tendon, and that treatment with the p38 MAPK inhibitor SB203580 would prevent this growth. Rats were treated with vehicle or SB203580, and subjected to synergist ablation by bilateral tenectomy of the Achilles tendon. Changes in histological and biochemical properties of plantaris tendons were analyzed 3, 7, or 28 days after overload, and comparisons were made to non-overloaded animals. By 28 days after overload, tendon mass had increased by 30% compared to non-overloaded samples, and cross-sectional area (CSA) increased by around 50%, with most of the change occurring in the neotendon. The expansion in CSA initially occurred through the synthesis of a hyaluronic acid rich matrix that was progressively replaced with mature collagen. Pericytes were present in areas of active tendon growth, but never in the original tendon ECM. Inhibition of p38 MAPK resulted in a profound decrease in IL6 expression, and had a modest effect on the expression of other ECM and cell proliferation genes, but had a negligible impact on overall tendon growth. The combined results from this study provided novel insights into tendon mechanobiology, and suggest that p38 MAPK signaling does not appear to be necessary for tendon growth in vivo.

No MeSH data available.


Representative cross-sections of plantaris tendons subjected to synergist ablation, stained with hematoxylin and eosin.(A) Low magnification view of the tendon, and high magnification views of (B) the original tendon and (C) the neotendon are shown. (D-I) Quantitative analysis of tendon sections: Cross-sectional area (CSA, in mm2) of (D) the original tendon, (E) the neotendon, and (F) the total tendon. Cell density (cells/mm2) of (G) the original tendon, (H) the neotendon, and (I) the total tendon. Values are mean±SD. N, 4 to 8 tendons for each group. Differences between groups were tested using a two-way ANOVA (α = 0.05) followed by Newman-Keuls post hoc sorting: a, different (P<0.05) from 3D vehicle; b, different (P<0.05) from 3D p38 MAPK inhibitor; c, different (P<0.05) from 7D vehicle; d, different (P<0.05) from 7D p38 MAPK inhibitor; e, different (P<0.05) from 28D vehicle. For reference, horizontal dashed line indicates wet mass of plantaris tendons that were not subjected to synergist ablation.
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pone.0120044.g003: Representative cross-sections of plantaris tendons subjected to synergist ablation, stained with hematoxylin and eosin.(A) Low magnification view of the tendon, and high magnification views of (B) the original tendon and (C) the neotendon are shown. (D-I) Quantitative analysis of tendon sections: Cross-sectional area (CSA, in mm2) of (D) the original tendon, (E) the neotendon, and (F) the total tendon. Cell density (cells/mm2) of (G) the original tendon, (H) the neotendon, and (I) the total tendon. Values are mean±SD. N, 4 to 8 tendons for each group. Differences between groups were tested using a two-way ANOVA (α = 0.05) followed by Newman-Keuls post hoc sorting: a, different (P<0.05) from 3D vehicle; b, different (P<0.05) from 3D p38 MAPK inhibitor; c, different (P<0.05) from 7D vehicle; d, different (P<0.05) from 7D p38 MAPK inhibitor; e, different (P<0.05) from 28D vehicle. For reference, horizontal dashed line indicates wet mass of plantaris tendons that were not subjected to synergist ablation.

Mentions: Morphologically, overload of the plantaris tendon generated a neotendon matrix that arose outward from the most superficial layers of the original tendon (Fig. 3A-C). Other than differences in CSA and density, p38 MAPK inhibition did not impact the general morphological features of tendons, and representative images from a control 3 day overloaded tendon are provided (Fig. 3A-C). For the original tendon region, the CSA of all groups was similar to non-overloaded tendons, and did not change in response to time after overload or treatment with p38 MAPK inhibitor (Fig. 3D). The CSA of the neotendon increased by greater than 50% in both vehicle and treatment groups by 7 days, but decreased by a similar magnitude for both groups between 7 and 28 days (Fig. 3E). Changes in whole tendon CSA generally followed the trends observed in the neotendon data (Fig. 3F). Neither time after overload nor treatment with p38 MAPK inhibitor impacted cell density overall, although the density of cells in the neotendon was considerably greater than what was observed in the original tendon (Fig. 3G-I).


p38 MAPK signaling in postnatal tendon growth and remodeling.

Schwartz AJ, Sarver DC, Sugg KB, Dzierzawski JT, Gumucio JP, Mendias CL - PLoS ONE (2015)

Representative cross-sections of plantaris tendons subjected to synergist ablation, stained with hematoxylin and eosin.(A) Low magnification view of the tendon, and high magnification views of (B) the original tendon and (C) the neotendon are shown. (D-I) Quantitative analysis of tendon sections: Cross-sectional area (CSA, in mm2) of (D) the original tendon, (E) the neotendon, and (F) the total tendon. Cell density (cells/mm2) of (G) the original tendon, (H) the neotendon, and (I) the total tendon. Values are mean±SD. N, 4 to 8 tendons for each group. Differences between groups were tested using a two-way ANOVA (α = 0.05) followed by Newman-Keuls post hoc sorting: a, different (P<0.05) from 3D vehicle; b, different (P<0.05) from 3D p38 MAPK inhibitor; c, different (P<0.05) from 7D vehicle; d, different (P<0.05) from 7D p38 MAPK inhibitor; e, different (P<0.05) from 28D vehicle. For reference, horizontal dashed line indicates wet mass of plantaris tendons that were not subjected to synergist ablation.
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pone.0120044.g003: Representative cross-sections of plantaris tendons subjected to synergist ablation, stained with hematoxylin and eosin.(A) Low magnification view of the tendon, and high magnification views of (B) the original tendon and (C) the neotendon are shown. (D-I) Quantitative analysis of tendon sections: Cross-sectional area (CSA, in mm2) of (D) the original tendon, (E) the neotendon, and (F) the total tendon. Cell density (cells/mm2) of (G) the original tendon, (H) the neotendon, and (I) the total tendon. Values are mean±SD. N, 4 to 8 tendons for each group. Differences between groups were tested using a two-way ANOVA (α = 0.05) followed by Newman-Keuls post hoc sorting: a, different (P<0.05) from 3D vehicle; b, different (P<0.05) from 3D p38 MAPK inhibitor; c, different (P<0.05) from 7D vehicle; d, different (P<0.05) from 7D p38 MAPK inhibitor; e, different (P<0.05) from 28D vehicle. For reference, horizontal dashed line indicates wet mass of plantaris tendons that were not subjected to synergist ablation.
Mentions: Morphologically, overload of the plantaris tendon generated a neotendon matrix that arose outward from the most superficial layers of the original tendon (Fig. 3A-C). Other than differences in CSA and density, p38 MAPK inhibition did not impact the general morphological features of tendons, and representative images from a control 3 day overloaded tendon are provided (Fig. 3A-C). For the original tendon region, the CSA of all groups was similar to non-overloaded tendons, and did not change in response to time after overload or treatment with p38 MAPK inhibitor (Fig. 3D). The CSA of the neotendon increased by greater than 50% in both vehicle and treatment groups by 7 days, but decreased by a similar magnitude for both groups between 7 and 28 days (Fig. 3E). Changes in whole tendon CSA generally followed the trends observed in the neotendon data (Fig. 3F). Neither time after overload nor treatment with p38 MAPK inhibitor impacted cell density overall, although the density of cells in the neotendon was considerably greater than what was observed in the original tendon (Fig. 3G-I).

Bottom Line: By 28 days after overload, tendon mass had increased by 30% compared to non-overloaded samples, and cross-sectional area (CSA) increased by around 50%, with most of the change occurring in the neotendon.Inhibition of p38 MAPK resulted in a profound decrease in IL6 expression, and had a modest effect on the expression of other ECM and cell proliferation genes, but had a negligible impact on overall tendon growth.The combined results from this study provided novel insights into tendon mechanobiology, and suggest that p38 MAPK signaling does not appear to be necessary for tendon growth in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States of America; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.

ABSTRACT
Tendon is a dynamic tissue whose structure and function is influenced by mechanical loading, but little is known about the fundamental mechanisms that regulate tendon growth and remodeling in vivo. Data from cultured tendon fibroblasts indicated that the p38 MAPK pathway plays an important role in tendon fibroblast proliferation and collagen synthesis in vitro. To gain greater insight into the mechanisms of tendon growth, and explore the role of p38 MAPK signaling in this process, we tested the hypotheses that inducing plantaris tendon growth through the ablation of the synergist Achilles tendon would result in rapid expansion of a neotendon matrix surrounding the original tendon, and that treatment with the p38 MAPK inhibitor SB203580 would prevent this growth. Rats were treated with vehicle or SB203580, and subjected to synergist ablation by bilateral tenectomy of the Achilles tendon. Changes in histological and biochemical properties of plantaris tendons were analyzed 3, 7, or 28 days after overload, and comparisons were made to non-overloaded animals. By 28 days after overload, tendon mass had increased by 30% compared to non-overloaded samples, and cross-sectional area (CSA) increased by around 50%, with most of the change occurring in the neotendon. The expansion in CSA initially occurred through the synthesis of a hyaluronic acid rich matrix that was progressively replaced with mature collagen. Pericytes were present in areas of active tendon growth, but never in the original tendon ECM. Inhibition of p38 MAPK resulted in a profound decrease in IL6 expression, and had a modest effect on the expression of other ECM and cell proliferation genes, but had a negligible impact on overall tendon growth. The combined results from this study provided novel insights into tendon mechanobiology, and suggest that p38 MAPK signaling does not appear to be necessary for tendon growth in vivo.

No MeSH data available.