In this study, we propose a method for quantitative prediction of changes in concentrations of a number of key signaling, structural and effector molecules within the extracellular matrix of tendon. To achieve this, we introduce the notion of elementary cell responses (ECRs). An ECR defines a normal reference secretion profile of a molecule by a tenocyte in response to the tenocyte’s local strain. ECRs are then coupled with a model for mechanical damage of tendon collagen fibers at different straining conditions of tendon and then scaled up to the tendon tissue level for comparison with experimental observations. Specifically, our model predicts relative changes in ECM concentrations of transforming growth factor beta, interleukin 1 beta, collagen type I, glycosaminoglycan, matrix metalloproteinase 1 and a disintegrin and metalloproteinase with thrombospondin motifs 5, with respect to tendon straining conditions that are consistent with the observations in the literature. In good agreement with a number of in vivo and in vitro observations, the model provides a logical and parsimonious explanation for how excessive mechanical loading of tendon can lead to under-stimulation of tenocytes and a degenerative tissue profile, which may well have bearing on a better understanding of tendon homeostasis and the origin of some tendinopathies.