Growth and Mechanobiology of the Achilles Enthesis in Mice

Entheses are connective tissues that connect tendon to bone, two vastly different hierarchical materials with different structural and mechanical properties. As a result of this material mismatch, entheses are prone to local peaks in mechanical stress (stress concentrations) that increase their susceptibility to overuse injuries, especially during rapid growth (postnatal maturation) and in young athletes. The enthesis matures postnatally in a mechanoadaptive process, similar to the growing bone, and forms a graded transition to dampen the stress concentrations at the attachment site. Despite decades of research, the key biological and mechanoadaptive processes that govern the adaptation of the enthesis under repeated loading and onset of injury during its postnatal maturation remain unknown.

The objective of this research was to investigate the role of mechanical and biological cues on the mechanoadaptation of growing and adult entheses. I did that through four main aims: (1) developing and confirming the feasibility and repeatability of a novel non-invasive in vivo model for repeated loading of the tendon and enthesis, using optogenetics; (2) investigating the age-dependent mechanicallyinduced structural and functional adaptation of the enthesis during growth and adulthood; (3) exploring the structural and functional relationships and possible mechanisms of damage (i.e., disrupted interdigitation vs. collagen denaturation) in disruption of the toughening mechanism of the maturing enthesis; and (4) identifying FGFs signaling, a known mediator of bone growth, as a critical regulator of the structural gradation, and therefore, mechanical properties of maturing entheses.

This study is innovative in taking an interdisciplinary approach to put forth a novel model for skeletal adaptation to loading during growth, elucidating the structural adaptation of maturing and adult enthesis under repeated loading, and proposing new biological pathways involved in the mechanoadaptation of the maturing enthesis. The results and tools developed in this work can be used to investigate the adaptation of the enthesis by investigating the mechanobiology of enthesis formation, with the longterm goal of improving the diagnosis and treatment of overuse injuries in maturing attachment.

Year	Entry
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Year

Entry

2005

Guilak F, Hung CT. Physical regulation of cartilage metabolism. In: Mow VC, Huiskes R, eds. Basic Orthopaedic Biomechanics & Mechano-Biology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:259-300.

2015

Jepsen KJ, Silva MJ, Vashishth D, Guo XE, van der Meulen MCH. Establishing biomechanical mechanisms in mouse models: practical guidelines for systematically evaluating phenotypic changes in the diaphyses of long bones. J Bone Miner Res. June 2015;30(6):951-966.

1990

Komi PV. Relevance of in vivo force measurements to human biomechanics. J Biomech. 1990;23(suppl 1):23-34.

2010

Fung DT, Wang VM, Andarawis-Puri N, Basta-Pljakic J, Li Y, Laudier DM, Sun HB, Jepsen KJ, Schaffler MB, Flatow EL. Early response to tendon fatigue damage accumulation in a novel in vivo model. J Biomech. January 19, 2010;43(2):274-279.

2020

Lin AH, Allan AN, Zitnay JL, Kessler JL, Yu SM, Weiss JA. Collagen denaturation is initiated upon tissue yield in both positional and energy-storing tendons. Acta Biomater. December 2020;118:153-160.