Discovery of Novel Wound Healing Mechanisms Using Mice Deficient In Specific Matrix Turnover Enzymes

Together with standard biochemical methods, the development of murine transgenic/knockout technologies has led to an extensive new knowledge base of the structure and function of proteins in development, growth and aging and also in human disease. In addition, transgenic mice can often display a range of 'unexpected' phenotypes, and we have found that detailed studies of these unpredicted effects can often provide novel insights into the integration of metabolic pathway networks and complex molecular structural assemblies. Our recent work on mice lacking one of two extracellular matrix turnover enzymes, (ADAMTS5 and Hyaluronan Synthase 1 (HAS1)) provides a good example of such unexpected discovery.

Firstly, our studies with mice lacking ADAMTS5 (a proteoglycan-cleaving proteinase) revealed an ulcerative dermal wound healing and a chronic tendinopathy phenotype and in each case excess chondroid-rich deposits were formed by progenitor cells at the wound sites. In vitro studies with adipose tissue derived stromal cells have uncovered a non-proteolytic function of ADAMTS5 in modulation of glucose uptake. A novel role for this protein in an endocytotic process, involving competitive interactions between ADAMTS5, LRP1 and GLUT4 will be discussed.

Secondly, our studies with mice lacking HAS1 (a glycosaminoglycan synthetase) also display severely impaired soft tissue repair capacity, with perturbed expression of genes (27 identified herein) linked to the IL‑17/IL‑6 signaling network. Bioinformatic pathway analyses revealed linkage of these disrupted pathways to chronic fibrosis and inflammation leading to a keloid type-wound healing response.