Abstract
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.
Highlights
Remodeling of the extracellular matrix is required for a range of normal physiological processes but is connected to a number of pathological conditions including arthritis, fibrosis and cancer [1,2,3,4]
To address the putative functional overlap between uPARAP and matrix metalloproteinases (MMPs)-2 we have studied the effects of uPARAP deficiency, MMP-2 deficiency and combined uPARAP and MMP-2 deficiency in mice, with special emphasis on bone development and homeostasis
Since uPARAP is expressed in bone and is a major player in the first-mentioned pathway [11,29], we wished to examine the longterm consequences of uPARAP deficiency for bone homeostasis, alone or in combination with MMP-2 deficiency
Summary
Remodeling of the extracellular matrix is required for a range of normal physiological processes but is connected to a number of pathological conditions including arthritis, fibrosis and cancer [1,2,3,4]. Bone formation occurs through two distinct processes known as endochondral ossification and intramembranous ossification. Most bones of the body, such as the long bones, develop through initial superficial intramembranous ossification followed by endochondral ossification to establish the cancellous core of the bone. Some flat bones of the skull on the other hand develop completely or partially through intramembranous ossification, which is characterized by bone formation directly within a soft connective tissue that is partially associated with a cartilage primordium [5,6,7]. Bone remodeling serves to replace damaged tissue with new tissue, and to adapt to changes in the mechanical stress imposed on the bone
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