Postnatal mechanical loading drives adaptation of tissues primarily through modulation of the non-collagenous matrix

Abstract

Mature connective tissues demonstrate highly specialised properties, remarkably adapted to meet their functional requirements. Tissue adaptation to environmental cues can occur throughout life and poor adaptation commonly results in injury. However, the temporal nature and drivers of functional adaptation remain undefined. Here, we explore functional adaptation and specialisation of mechanically loaded tissues using tendon; a simple aligned biological composite, in which the collagen (fascicle) and surrounding predominantly non-collagenous matrix (interfascicular matrix) can be interrogated independently. Using an equine model of late development, we report the first phase-specific analysis of biomechanical, structural and compositional changes seen in functional adaptation, demonstrating adaptation occurs postnatally, following mechanical loading, and is almost exclusively localised to the non-collagenous interfascicular matrix. These novel data redefine adaptation in connective tissue, highlighting the fundamental importance of non-collagenous matrix and suggesting that regenerative medicine strategies should change focus from the fibrous to the non-collagenous matrix of tissue.

Structure-function specialisation of the interfascicular matrix in the human achilles tendon

“…TGF-β signalling is essential for tendon development, and is expressed predominantly within the IFM of developing and adult tendons [61] , [62] , [63] . Indeed, our recent work demonstrates upregulation of TGF-β in the IFM of the energy storing equine SDFT upon commencement of loading during development [29] . However, TGF-β signalling has also been shown to be dysregulated in several age-associated diseases, including atherosclerosis, neurodegenerative diseases and arthritis, and is upregulated in tendon injury [ 64 , 65 ].…”

“…TGF-β has also been identified as a master regulator of fibrosis [67] , and it is therefore likely that dysregulation of TGF-β signalling in the old Achilles drives the increase in fibrosis-associated proteins within the IFM. We have previously shown that TGF-β regulation of ECM organisation during development is specific to energy-storing tendons, and is likely to be induced by mechanical loading [29] , suggesting that the dysregulation observed during ageing may result from an altered loading environment within the Achilles tendon, either due to changes in activity levels or an age-related deterioration of tendon structure.…”

“…Fascicle and IFM proteins were identified, searching against the UniHuman reviewed database ( http://www.uniprot.org/proteomes/ ) using parameters and filters as described previously [29] (Peaks® 8.5 PTM software; Bioinformatics Solutions, Canada). Label-free quantification was performed separately for IFM and fascicles from each tendon and age group (Peaks® 8.5 PTM software).…”

Structure-function Specialisation of the Interfascicular Matrix in the Human Achilles Tendon

“…TGF-β signalling is essential for tendon development, and is expressed predominantly within the IFM of developing and adult tendons,[43-45]. Indeed, our recent work demonstrates upregulation of TGF-β in the IFM of the energy storing equine SDFT upon commencement of loading during development,[26]. However, TGF-β signalling has also been shown to be dysregulated in several age-associated diseases, including atherosclerosis, neurodegenerative diseases and arthritis, and is upregulated in tendon injury,[46, 47].…”

“…Fascicle and IFM proteins were identified, searching against the UniHuman reviewed database (http://www.uniprot.org/proteomes/) using parameters and filters as described previously,[26] (Peaks® 8.5 PTM software; Bioinformatics Solutions, Canada). Label-free quantification was performed separately for IFM and fascicles from each tendon and age group (Peaks® 8.5 PTM software).…”