Tenocytes serve to synthesize and maintain collagen fibrils and other extracellular matrix proteins in tendon. Despite the high prevalence of tendon injury, the underlying biologic mechanisms of postnatal tendon growth and repair are not well understood. IGF1 plays an important role in the growth and remodeling of numerous tissues but less is known about IGF1 in tendon. We hypothesized that IGF1 signaling is required for proper tendon growth in response to mechanical loading through regulation of collagen synthesis and cell proliferation. To test this hypothesis, we conditionally deleted the IGF1 receptor (IGF1R) in scleraxis (Scx)‐expressing tenocytes using a tamoxifen‐inducible Cre‐recombinase system and caused tendon growth in adult mice via mechanical overload of the plantaris tendon. Compared with control Scx‐expressing IGF1R‐positive (Scx:IGF1R+) mice, in which IGF1R is present in tenocytes, mice that lacked IGF1R in their tenocytes [Scx‐expressing IGF1R‐negative (Scx:IGF1RΔ) mice] demonstrated reduced cell proliferation and smaller tendons in response to mechanical loading. Additionally, we identified that both the PI3K/protein kinase B and ERK pathways are activated downstream of IGF1 and interact in a coordinated manner to regulate cell proliferation and protein synthesis. These studies indicate that IGF1 signaling is required for proper postnatal tendon growth and support the potential use of IGF1 in the treatment of tendon disorders.—Disser, N. P., Sugg, K. B., Talarek, J. R., Sarver, D. C., Rourke, B. J., Mendias, C. L. Insulin‐like growth factor 1 signaling in tenocytes is required for adult tendon growth. FASEB J. 33, 12680–12695 (2019). http://www.fasebj.org
Platelet-derived growth factor receptor (PDGFR) signaling plays an important role in the fundamental biological activities of many cells that compose musculoskeletal tissues. However, little is known about the role of PDGFR signaling during tendon growth and remodeling in adult animals. Using the hindlimb synergist ablation model of tendon growth, our objectives were to determine the role of PDGFR signaling in the adaptation of tendons subjected to a mechanical growth stimulus, as well as to investigate the biological mechanisms behind this response. We demonstrate that both PDGFRs, PDGFRα and PDGFRβ, are expressed in tendon fibroblasts and that the inhibition of PDGFR signaling suppresses the normal growth of tendon tissue in response to mechanical growth cues due to defects in fibroblast proliferation and migration. We also identify membrane type-1 matrix metalloproteinase (MT1-MMP) as an essential proteinase for the migration of tendon fibroblasts through their extracellular matrix. Furthermore, we report that MT1-MMP translation is regulated by phosphoinositide 3-kinase/Akt signaling, while ERK1/2 controls posttranslational trafficking of MT1-MMP to the plasma membrane of tendon fibroblasts. Taken together, these findings demonstrate that PDGFR signaling is necessary for postnatal tendon growth and remodeling and that MT1-MMP is a critical mediator of tendon fibroblast migration and a potential target for the treatment of tendon injuries and diseases.
Injured tendons heal through the formation of a fibrovascular scar that has inferior mechanical properties compared to native tendon tissue. Reducing inflammation that occurs as a result of the injury could limit scar formation and improve functional recovery of tendons. Prostaglandin D2 (PGD2) plays an important role in promoting inflammation in some injury responses and chronic disease processes, and the inhibition of PGD2 has improved healing and reduced disease burden in animal models and early clinical trials. Based on these findings, we sought to determine the role of PGD2 signaling in the healing of injured tendon tissue. We tested the hypothesis that a potent and specific inhibitor of hematopoietic PGD synthase (HPGDS), GSK2894631A, would improve the recovery of tendons of adult male rats following an acute tenotomy and repair. To test this hypothesis, we performed a full‐thickness plantaris tendon tenotomy followed by immediate repair and treated rats twice daily with either 0, 2, or 6 mg/kg of GSK2894631A. Tendons were collected either 7 or 21 days after surgical repair, and mechanical properties of tendons were assessed along with RNA sequencing and histology. While there were some differences in gene expression across groups, the targeted inhibition of HPGDS did not impact the functional repair of tendons after injury, as HPGDS expression was surprisingly low in injured tendons. These results indicate that PGD2 signaling does not appear to be important in modulating the repair of injured tendon tissue.
Tendon fibroblasts, or tenocytes, are the main cell type in tendon and serve to synthesize and maintain collagen fibrils and other extracellular matrix proteins within the tissue. Despite the high prevalence of tendon injury, the underlying biological mechanisms of postnatal tendon growth and repair are not well understood. Insulin‐like growth factor (IGF‐1) signaling is stimulated by growth hormone (GH) and promotes the growth and development of many different tissue types. While IGF‐1 is a potent hypertrophic signaling molecule in skeletal muscle, less is known about the role of IGF‐1 in tendon biology. Therefore, the purpose of this study was to determine the importance of IGF‐1 signaling in postnatal tendon growth. Our hypothesis was that IGF‐1 signaling is required for the response of tendon to a mechanical load stimulus. To test this hypothesis, we used both in vitro studies of cultured tenocytes, and in vivo studies using genetically modified mice that allowed us to delete the IGF‐1 receptor (IGF1R) specifically in tenocytes. Treatment of tenocytes in vitro with IGF‐1 increased the expression of Mki67 transcript levels after 24 hours, and resulted in activation of the Akt and ERK1/2 pathways. When tenocyte proliferative activity was measured, cells treated with IGF‐1 displayed increased proliferation compared to controls, but inhibition of ERK prevented the IGF‐1‐mediated increase in cell proliferation and Mki67 (Ki67) expression. Inhibition of Akt signaling did not impact tenocyte proliferation or Mki67 expression. In addition, treatment of tenocytes with IGF1 increased the rate of protein synthesis and ribosomal RNA expression. Analysis of mechanically overloaded plantaris tendons in vivo revealed significantly reduced size of the neotendon matrix which forms around the original tendon in response to mechanical loads, and total tendon cross‐sectional area (CSA) at 14 days in the IGF‐1 knockdown mice compared to the controls. This was accompanied by decreased number of proliferating cells and proteins involved in cell proliferation and initiation of translation, as measured by proteomic analysis. The results of this work support IGF‐1 signaling as a fundamental component of postnatal tendon growth in response to mechanical loading, specifically through the regulation of ERK1/2‐dependent tenocyte proliferation and initiation of protein synthesis. Further studies of the growth factors and proteins involved, and the potential to evaluate IGF‐1 to promote tendon regeneration, are warranted.Support or Funding InformationNIH R01‐AR063649 and F32‐AR067086.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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