A crucial role for matrix metalloproteinase 2 in osteocytic canalicular formation and bone metabolism.
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.
Inoue
Keiichi
K
Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
Mikuni-Takagaki
Yuko
Y
Oikawa
Kaoru
K
Itoh
Takeshi
T
Inada
Masaki
M
Noguchi
Takanori
T
Park
Jin-Sung
JS
Onodera
Takashi
T
Krane
Stephen M
SM
Noda
Masaki
M
Itohara
Shigeyoshi
S
D000818:Animals; D017209:Apoptosis; D001846:Bone Development; D016025:Bone Transplantation; D001842:Bone and Bones / Q000166:cytology* / Q000378:metabolism*; D002113:Calcification, Physiologic / Q000502:physiology; D002454:Cell Differentiation; D005145:Face / Q000002:abnormalities; D020778:Matrix Metalloproteinase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000378:metabolism; D010011:Osteocytes / Q000166:cytology* / Q000378:metabolism*; D010012:Osteogenesis
D020778:Matrix Metalloproteinase 2