INVESTIGATION OF THE EFFECTS OF THE GH/IGF-1 AXIS ON TENDON MAINTENANCE AND REPAIR THROUGH COLLAGEN SYNTHESIS IN TRANSGENIC MICE.

• Grant number: 24/02974-7
• Support Opportunities: Regular Research Grants
• Start date: June 01, 2025
• End date: May 31, 2027
• Field of knowledge: Health Sciences - Physical Education
• Principal Investigator: Diego Pulzatto Cury
• Grantee: Diego Pulzatto Cury
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Fernando José Dias ; Jose Donato Junior ; Rodrigo Labat Marcos

Abstract

Tendons play a fundamental role in connecting muscle belly to bone, transmitting contraction forces to generate movement. Mainly composed of collagen, tendons consist of approximately 95% type I collagen and less than 10% type III collagen. Conditions such as tendinopathies, aging, and physical activity increase susceptibility to injuries. The Achilles tendon is frequently injured, accounting for approximately 45% of musculoskeletal disorders in the United States, resulting in an average treatment cost of around $114 billion per year. Treatment immobilization time can range from 84 to 270 days, leading to significant socioeconomic problems. Due to the composition of tendons and knowing that previous studies have shown actions of the GH/IGF-1 axis on collagen synthesis, but never separately, our main objective is to understand for the first time the role of GH and IGF-1, individually, in collagen synthesis in tendon tissue. Materials and Methods: Various mice models will be used, including bGH mice with increased circulating levels of GH and IGF-1, little/little mice deficient in GH and IGF-1, as well as AlbuminGHR mice deficient in GHR only in hepatocytes with very low circulating levels of IGF-1 and normal GH secretion. Wild-type C57BL/6 mice will be used as controls. If the findings are promising, Col1a2Cre-ER::GHRflox/flox mice will be used to inactivate GH and IGF-1 receptors only in fibroblasts, including adult mouse tendons. Thus, it is hoped to generate a mouse for the first time that allows tissue-specific manipulation of these receptors in tendons. Thus, the direct effects of these hormones can be tested without alterations in circulating levels of GH or IGF-1. Experiments without tendon rupture will be performed to see the role of the mentioned hormones and with complete rupture to evaluate the effect during tissue repair. Analyses will be conducted through transmission electron microscopy for morphological understanding of collagen fibrils, as well as western blotting and RT-qPCR experiments to understand for the first time the true isolated role of GH and IGF-1 in collagen synthesis and whether they act directly or indirectly in tendon tissue. Preliminary Results: We analyzed, through transmission electron microscopy, tendons from a small group of control animals, bGH, little/little, and AlbuminGHR. We obtained some insights into possible discoveries throughout the work, but so far, IGF-1 deficiency, regardless of GH circulating levels, has been shown to cause disorganization in collagen secretion. It is worth noting that this will be the first research grant requested by the responsible researcher who was recently hired as a faculty member at ICB/USP. Thus, FAPESP's support will be crucial for the creation of the Electron Microscopy and Musculoskeletal Disorders Laboratory, which will specialize in the study of physiology and pathology related to the musculoskeletal system. (AU)