Hypoxia-driven secretion of extracellular matrix proteins in the exosomes reflects the asymptomatic pathology of rotator cuff tendinopathies

The major hallmark of rotator cuff tendinopathies (RCT) is the disorganization of tendon extracellular matrix (ECM) which is due to decrease in the collagen I-to-collagen III ratio. In addition, the pathology of tendon matrisome remains asymptomatic and hypoxia has been identified to be the priming signal to initiate the molecular pathology of RCT. Also, the secretome content of hypoxia challenged tendon cells (tenocytes) reflects the pathological status of RCT. With this background, the present study was designed to establish the expression status and the molecular crosstalk of the ECM component proteins contained in the exosomes of the hypoxia challenged swine tenocytes. The mass spectrometry analysis revealed the upregulation of COL1A2, P4HA1, PRDX2, P3H1, COL6A1, PPIB, LCN1, and COL3A1 and the downregulation of COLA12, PDIA4, COLG, FN1, CTSK, and TNC in the exosomes of hypoxic tenocytes. These proteins interact with diverse proteins and operate multiple pathways associated with ECM homeostasis and repair as determined by NetworkAnalyst. The functional analysis of these proteins reflects the pathology of tendon ECM which is correlated with the asymptomatic phase of RCT. Understanding the signaling mediated by these proteins would reveal the underlying molecular pathology and offers translational significance in the diagnosis/management of RCT.