A Crucial Role for Matrix Metalloproteinase 2 in Osteocytic Canalicular Formation and Bone Metabolism

Keiichi Inoue,Yuko Mikuni-Takagaki,Kaoru Oikawa,Takeshi Itoh,Masaki Inada,Takanori Noguchi,Jin-Sung Park,Takashi Onodera,Stephen M Krane,Masaki Noda,Shigeyoshi Itohara

doi:10.1074/jbc.m607290200

Abstract

Extracellular matrix production and degradation by bone cells are critical steps in bone metabolism. Mutations of the gene encoding MMP-2, an extracellular matrix-degrading enzyme, are associated with a human genetic disorder characterized by subcutaneous nodules, arthropathy, and focal osteolysis. It is not known how the loss of MMP-2 function results in the pathology. Here, we show that Mmp2(-/-) mice exhibited opposing bone phenotypes caused by an impaired osteocytic canalicular network. Mmp2(-/-) mice showed decreased bone mineral density in the limb and trunk bones but increased bone volume in the calvariae. In the long bones, there was moderate disruption of the osteocytic networks and reduced bone density throughout life, whereas osteoblast and osteoclast function was normal. In contrast, aged but not young Mmp2(-/-) mice had calvarial sclerosis with osteocyte death. Severe disruption of the osteocytic networks preceded osteocyte loss in Mmp2(-/-) calvariae. Successful transplantation of wild-type periosteum restored the osteocytic canalicular networks in the Mmp2(-/-) calvariae, suggesting local roles of MMP-2 in determining bone phenotypes. Our results indicate that MMP-2 plays a crucial role in forming and maintaining the osteocytic canalicular network, and we propose that osteocytic network formation is a determinant of bone remodeling and mineralization.

Highlights

Bone is continuously remodeled to adopt a volume appropriate for the local environment; the amount of bone deposited depends on the balance between bone formation and resorption by bone cells, osteoblasts, osteoclasts, and osteocytes [1]
Consistent with these findings, cesses after being embedded in the bone matrix and differentiosteoblastic activities, represented by mineral apposition rate (MAR) and the ratio of ating into mature osteocytes. These findings suggest that bone formation rate to bone surface (BFR/BS), were signifi- matrix metalloproteinases (MMPs)-2 contributes to form and/or maintain the osteocytic cantly increased at 55 weeks of age (Fig. 5D), suggesting that the network
Sclerostin must accumulate in the osteocytic lacunae in Mmp2Ϫ/Ϫ mouse calvariae because the canalicular networks are ablated or not formed. These results suggest that interrupted transport of sclerostin from osteocytes to osteoblasts removes the inhibition of osteoblastic bone formation and, in addition, augments apoptosis in Mmp2Ϫ/Ϫ calvariae

Summary

Introduction

Bone is continuously remodeled to adopt a volume appropriate for the local environment; the amount of bone deposited depends on the balance between bone formation and resorption by bone cells, osteoblasts, osteoclasts, and osteocytes [1]. Cultures of bone marrow cells obtained from Mmp2Ϫ/Ϫ mice developed normally mineralized nodules and tartrate-resistant acid phosphatase-positive osteoclasts in vitro (Fig. 4A). To examine the role of MMP-2 in the osteocytic netaugmented bone formation resulted in the sclerosis of aged work, we stained bone sections using the Bodian method to Mmp2Ϫ/Ϫ calvariae.

Results

Conclusion