Regulation and function of the AP-1 target gene collagenase-3 (MMP-13)

Matrix metalloproteinases are proposed to play an important role during physiological processes that require tissue remodelling, such as embryogenesis organogenesis, angiogenesis and wound healing, and pathological processes, for example chronic inflammation and tumour progression. Our laboratory has been particularly interested in a subgroup of this family, the interstitial collagenases MMP-1 and MMP-13, as we have identified them as the first target genes of AP-1. We detected MMP-13 expression in murine osteoblasts during embryonic development and in adult mice (MMP-1 is not expressed in mice) providing strong evidence that collagenase activity is required for bone development and remodelling. Expression of MMP-13 is controlled by parathyroid hormone (PTH), which is mediated by physical interaction between AP-1 and a “master regulator“ of osteoblast differentiation and bone development, the transcription factor Cbfa1.

To unequivocally define the function of MMP-13 in bone homeostasis MMP-13-deficient mice were generated. These mice exhibit abnormal skeletal growth plate development due to delayed exit of differentiated chondrocytes from the growth plate and increased trabecular bone mass in long bones. Two major components of the cartilage matrix, collagen type 2 and aggrecan, could be identified as in vivo substrates for MMP-13, whose degradation is a coordinated process in which MMP-13 works synergistically with MMP-9. Mice lacking both enzymes have a severely impaired endochondral ossification process and result in drastically shortened bones, supporting the hypothesis that proper ECM remodelling is required for normal endochondral ossification.