Targeted disruption of the osteoblast/osteocyte factor 45 gene (OF45) results in increased bone formation and bone mass.
We have previously described osteoblast/osteocyte factor 45 (OF45), a novel bone-specific extracellular matrix protein, and demonstrated that its expression is tightly linked to mineralization and bone formation. In this report, we have cloned and characterized the mouse OF45 cDNA and genomic region. Mouse OF45 (also called MEPE) was similar to its rat orthologue in that its expression was increased during mineralization in osteoblast cultures and the protein was highly expressed within the osteocytes that are imbedded within bone. To further determine the role of OF45 in bone metabolism, we generated a targeted mouse line deficient in this protein. Ablation of OF45 resulted in increased bone mass. In fact, disruption of only a single allele of OF45 caused significantly increased bone mass. In addition, knockout mice were resistant to aging-associated trabecular bone loss. Cancellous bone histomorphometry revealed that the increased bone mass was the result of increased osteoblast number and osteoblast activity with unaltered osteoclast number and osteoclast surface in knockout animals. Consistent with the bone histomorphometric results, we also determined that OF45 knockout osteoblasts produced significantly more mineralized nodules in ex vivo cell cultures than did wild type osteoblasts. Osteoclastogenesis and bone resorption in ex vivo cultures was unaffected by OF45 mutation. We conclude that OF45 plays an inhibitory role in bone formation in mouse.
Gowen
Lori C
LC
Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, Connecticut 06340, USA.
Petersen
Donna N
DN
Mansolf
Amy L
AL
Qi
Hong
H
Stock
Jeffrey L
JL
Tkalcevic
George T
GT
Simmons
Hollis A
HA
Crawford
David T
DT
Chidsey-Frink
Kristen L
KL
Ke
Hua Zhu
HZ
McNeish
John D
JD
Brown
Thomas A
TA
D000818:Animals; D001483:Base Sequence; D001846:Bone Development / Q000235:genetics*; D002478:Cells, Cultured; D003001:Cloning, Molecular; D017931:DNA Primers; D018076:DNA, Complementary; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D015870:Gene Expression; D006023:Glycoproteins; D008969:Molecular Sequence Data; D009929:Organ Size / Q000235:genetics*; D010641:Phenotype; D010750:Phosphoproteins; D051381:Rats
D017931:DNA Primers; D018076:DNA, Complementary; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C417185:Mepe protein, rat; D010750:Phosphoproteins