In the late stages of the tissue repair process, as well as during normal tissue turnover, tissue homeostasis may rely mostly on autocrine mechanisms. Accordingly, we have cultured normal human fibroblasts on plastic surfaces and within three-dimensional collagen gels in order to study, in this environment, the action of autologous medium conditioned by the same cells. We have observed that inside collagen gels the autologous medium strongly restrains cell proliferation, due to fibroblast-secreted growth factors, whose inhibitory effect can be annulled by suramin. Furthermore, concerning extracellular matrix formation, conditioned medium has no effect on novel collagen synthesis, while it up-regulates collagenase MMP-1 only in cultures on plastic. On the other hand, it strongly inhibits the secretion of the collagenase inhibitor TIMP-1, irrespective of the substratum. This effect is completely blocked by SE 203580, an inhibitor of the p38 MAP kinase. The above suggest the presence of an autoregulatory mechanism involved in tissue homeostasis.