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.
Highlights
Tendon plays a vital role in the musculoskeletal system by transmitting forces between skeletal muscle and bone
Hindlimb synergist ablation is a commonly used technique for the study of skeletal muscle hypertrophy in mice and rats [12,13,14,15,16,17,18], and we recently demonstrated that this model is informative to study tendon growth in mice [9]
The main findings from the mouse model of plantaris tendon growth were that fibroblasts in the core of the tendon do not re-enter the cell cycle to contribute to adaptations following overload, and the majority of growth occurs due to expansion of tissue in the outer epitenon/peritenon area of the tendon, which is characterized by an abundance of cells actively undergoing mitosis [9]
Summary
Tendon plays a vital role in the musculoskeletal system by transmitting forces between skeletal muscle and bone. We previously reported that blocking the p38 MAPK pathway had a more profound inhibitory effect on adult tendon fibroblast proliferation and type I collagen synthesis than inhibition of the Smad2/3 pathway [7], suggesting that p38 MAPK may play an important role in TGF-b superfamily mediated growth and remodeling of tendon. Outbred strains of rats are 10 to 30 times larger than mice, have more diverse genetic make-up, and have greater sophistication in the anatomical ultrastructure and mechanical properties of tendons, which enhances the ability of rat models to be used for translational studies [19, 20]. We tested the hypothesis that treatment with SB203580 would prevent the normal growth and adaptation of tendon subjected to mechanical overload
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