Madsen, Daniel H9; Jürgensen, Henrik J10; Ingvarsen, Signe9; Melander, Maria C5; Albrechtsen, Reidar11; Hald, Andreas12; Holmbeck, Kenn5; Bugge, Thomas H5; Behrendt, Niels9; Engelholm, Lars H13
1 Behrendt Group, BRIC Research Groups, BRIC, Københavns Universitet2 BRIC, BRIC, Københavns Universitet3 Engelholm Group, BRIC Research Groups, BRIC, Københavns Universitet4 Behrendt Group, BRIC, Faculty of Health and Medical Sciences, Københavns Universitet5 unknown6 Kveiborg Group, BRIC, Faculty of Health and Medical Sciences, Københavns Universitet7 Porse Group, BRIC Research Groups, BRIC, Københavns Universitet8 Department of Biology, Faculty of Science, Københavns Universitet9 Behrendt Group, BRIC, Faculty of Health and Medical Sciences, Københavns Universitet10 Behrendt Group, BRIC Research Groups, BRIC, Københavns Universitet11 Kveiborg Group, BRIC, Faculty of Health and Medical Sciences, Københavns Universitet12 Porse Group, BRIC Research Groups, BRIC, Københavns Universitet13 Department of Biology, Faculty of Science, Københavns Universitet
A well-coordinated remodeling of uncalcified collagen matrices is a pre-requisite for bone development and homeostasis. Collagen turnover proceeds through different pathways, either involving extracellular reactions exclusively, or being dependent on endocytic processes. Extracellular collagen degradation requires the action of secreted or membrane attached collagenolytic proteases, whereas the alternative collagen degradation pathway proceeds intracellularly after receptor-mediated uptake and delivery to the lysosomes. In this study we have examined the functional interplay between the extracellular collagenase, MMP-2, and the endocytic collagen receptor, uPARAP, by generating mice with combined deficiency of both components. In both uPARAP-deficient and MMP-2-deficient adult mice the length of the tibia and femur was decreased, along with a reduced bone mineral density and trabecular bone quality. An additional decrease in bone length was observed when combining the two deficiencies, pointing to both components being important for the remodeling processes in long bone growth. In agreement with results found by others, a different effect of MMP-2 deficiency was observed in the distinct bone structures of the calvaria. These membranous bones were found to be thickened in MMP-2-deficient mice, an effect likely to be related to an accompanying defect in the canalicular system. Surprisingly, both of the latter defects in MMP-2-deficient mice were counteracted by concurrent uPARAP deficiency, demonstrating that the collagen receptor does not support the same matrix remodeling processes as the MMP in the growth of the skull. We conclude that both uPARAP and MMP-2 take part in matrix turnover processes important for bone growth. However, in some physiological situations, these two components do not support the same step in the growth process.
Plos One, 2013, Vol 8, Issue 8
Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't