Mechanotransduction in bone does not require a functional cyclooxygenase-2 (COX-2) gene

Imranul Alam, Stuart J. Warden, Alexander Robling, Charles H. Turner

Research output: Contribution to journalArticle

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Abstract

COX-2 is a key enzyme involved in the response of bone to loading. However, using mice with a null mutation of the COX-2 gene, we found that a functional COX-2 gene is not required for mechanotransduction. This paradoxical finding may have resulted, in part, from mechanically induced COX-1 activity. Introduction: Cyclooxygenase-2 (COX-2) is an important mediator in the response of bone to mechanical loading, with pharmacological inhibition of COX-2 effectively eliminating or reducing mechanically induced bone formation. In this study, we further investigated the role of COX-2 in skeletal mechanotransduction using a genetic approach. The aim was to compare the skeletal responsiveness of COX-2 homozygous mutant (COX-2-/-) and wildtype control (COX-2 +/+) mice to investigate whether a functional COX-2 gene is necessary for mechanotransduction. Materials and Methods: Adult female COX-2 +/+ and COX-2-/- mice on a C57BL/6×129/ola background were studied using the ulna axial loading model. The response to 2 days of loading for 120 cycles/day at 2 Hz was measured histomorphometrically. Phenotypic characterization of the femurs in these mice was also performed. In a separate group of animals, the expression of the remaining COX isozyme, COX-1, was assessed using real-time RT-PCR 4 h after one bout of 120 loading cycles. Results: Null mutation of the COX-2 gene resulted in a consistent femoral phenotype of reduced bone mass, altered architecture, and inferior mechanical properties. Many of these differences were nullified after adjustment for body weight. Nevertheless, body weight-corrected values showed a consistent trend of reduced mechanical properties in COX-2-/- mice. Genotype did not influence the response to mechanical loading, with no histomorphometric differences being found between COX-2+/+ and COX-2-/- mice. Real-time RT-PCR showed COX-2-/- mice to express significantly greater COX-1 expression in loaded ulnas than in loaded ulnas in COX-2 +/+ mice. There were no differences in COX-1 expression in nonloaded ulnas. Conclusions: A functional COX-2 gene was not found to be required for skeletal mechanotransduction. This is in contrast to previous pharmacological studies showing that COX-2 is critical to the response of bone to loading. Investigating a potential reason for the absence of a genotype difference in this study, we found that mice with a null mutation in the COX-2 gene possess inductive skeletal COX-1 expression.

Original languageEnglish
Pages (from-to)438-446
Number of pages9
JournalJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Volume20
Issue number3
DOIs
StatePublished - Mar 2005

Fingerprint

Cyclooxygenase 2
Bone and Bones
Genes
Ulna
Mutation
Real-Time Polymerase Chain Reaction
Genotype
Body Weight
Pharmacology
Weight-Bearing
Thigh
Osteogenesis
Femur
Isoenzymes
Mouse Ptgs2 protein

Keywords

  • Bone adaptation
  • Knockout
  • Mechanical loading
  • Prostaglandins

ASJC Scopus subject areas

  • Surgery

Cite this

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title = "Mechanotransduction in bone does not require a functional cyclooxygenase-2 (COX-2) gene",
abstract = "COX-2 is a key enzyme involved in the response of bone to loading. However, using mice with a null mutation of the COX-2 gene, we found that a functional COX-2 gene is not required for mechanotransduction. This paradoxical finding may have resulted, in part, from mechanically induced COX-1 activity. Introduction: Cyclooxygenase-2 (COX-2) is an important mediator in the response of bone to mechanical loading, with pharmacological inhibition of COX-2 effectively eliminating or reducing mechanically induced bone formation. In this study, we further investigated the role of COX-2 in skeletal mechanotransduction using a genetic approach. The aim was to compare the skeletal responsiveness of COX-2 homozygous mutant (COX-2-/-) and wildtype control (COX-2 +/+) mice to investigate whether a functional COX-2 gene is necessary for mechanotransduction. Materials and Methods: Adult female COX-2 +/+ and COX-2-/- mice on a C57BL/6×129/ola background were studied using the ulna axial loading model. The response to 2 days of loading for 120 cycles/day at 2 Hz was measured histomorphometrically. Phenotypic characterization of the femurs in these mice was also performed. In a separate group of animals, the expression of the remaining COX isozyme, COX-1, was assessed using real-time RT-PCR 4 h after one bout of 120 loading cycles. Results: Null mutation of the COX-2 gene resulted in a consistent femoral phenotype of reduced bone mass, altered architecture, and inferior mechanical properties. Many of these differences were nullified after adjustment for body weight. Nevertheless, body weight-corrected values showed a consistent trend of reduced mechanical properties in COX-2-/- mice. Genotype did not influence the response to mechanical loading, with no histomorphometric differences being found between COX-2+/+ and COX-2-/- mice. Real-time RT-PCR showed COX-2-/- mice to express significantly greater COX-1 expression in loaded ulnas than in loaded ulnas in COX-2 +/+ mice. There were no differences in COX-1 expression in nonloaded ulnas. Conclusions: A functional COX-2 gene was not found to be required for skeletal mechanotransduction. This is in contrast to previous pharmacological studies showing that COX-2 is critical to the response of bone to loading. Investigating a potential reason for the absence of a genotype difference in this study, we found that mice with a null mutation in the COX-2 gene possess inductive skeletal COX-1 expression.",
keywords = "Bone adaptation, Knockout, Mechanical loading, Prostaglandins",
author = "Imranul Alam and Warden, {Stuart J.} and Alexander Robling and Turner, {Charles H.}",
year = "2005",
month = "3",
doi = "10.1359/JBMR.041124",
language = "English",
volume = "20",
pages = "438--446",
journal = "Journal of Bone and Mineral Research",
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TY - JOUR

T1 - Mechanotransduction in bone does not require a functional cyclooxygenase-2 (COX-2) gene

AU - Alam, Imranul

AU - Warden, Stuart J.

AU - Robling, Alexander

AU - Turner, Charles H.

PY - 2005/3

Y1 - 2005/3

N2 - COX-2 is a key enzyme involved in the response of bone to loading. However, using mice with a null mutation of the COX-2 gene, we found that a functional COX-2 gene is not required for mechanotransduction. This paradoxical finding may have resulted, in part, from mechanically induced COX-1 activity. Introduction: Cyclooxygenase-2 (COX-2) is an important mediator in the response of bone to mechanical loading, with pharmacological inhibition of COX-2 effectively eliminating or reducing mechanically induced bone formation. In this study, we further investigated the role of COX-2 in skeletal mechanotransduction using a genetic approach. The aim was to compare the skeletal responsiveness of COX-2 homozygous mutant (COX-2-/-) and wildtype control (COX-2 +/+) mice to investigate whether a functional COX-2 gene is necessary for mechanotransduction. Materials and Methods: Adult female COX-2 +/+ and COX-2-/- mice on a C57BL/6×129/ola background were studied using the ulna axial loading model. The response to 2 days of loading for 120 cycles/day at 2 Hz was measured histomorphometrically. Phenotypic characterization of the femurs in these mice was also performed. In a separate group of animals, the expression of the remaining COX isozyme, COX-1, was assessed using real-time RT-PCR 4 h after one bout of 120 loading cycles. Results: Null mutation of the COX-2 gene resulted in a consistent femoral phenotype of reduced bone mass, altered architecture, and inferior mechanical properties. Many of these differences were nullified after adjustment for body weight. Nevertheless, body weight-corrected values showed a consistent trend of reduced mechanical properties in COX-2-/- mice. Genotype did not influence the response to mechanical loading, with no histomorphometric differences being found between COX-2+/+ and COX-2-/- mice. Real-time RT-PCR showed COX-2-/- mice to express significantly greater COX-1 expression in loaded ulnas than in loaded ulnas in COX-2 +/+ mice. There were no differences in COX-1 expression in nonloaded ulnas. Conclusions: A functional COX-2 gene was not found to be required for skeletal mechanotransduction. This is in contrast to previous pharmacological studies showing that COX-2 is critical to the response of bone to loading. Investigating a potential reason for the absence of a genotype difference in this study, we found that mice with a null mutation in the COX-2 gene possess inductive skeletal COX-1 expression.

AB - COX-2 is a key enzyme involved in the response of bone to loading. However, using mice with a null mutation of the COX-2 gene, we found that a functional COX-2 gene is not required for mechanotransduction. This paradoxical finding may have resulted, in part, from mechanically induced COX-1 activity. Introduction: Cyclooxygenase-2 (COX-2) is an important mediator in the response of bone to mechanical loading, with pharmacological inhibition of COX-2 effectively eliminating or reducing mechanically induced bone formation. In this study, we further investigated the role of COX-2 in skeletal mechanotransduction using a genetic approach. The aim was to compare the skeletal responsiveness of COX-2 homozygous mutant (COX-2-/-) and wildtype control (COX-2 +/+) mice to investigate whether a functional COX-2 gene is necessary for mechanotransduction. Materials and Methods: Adult female COX-2 +/+ and COX-2-/- mice on a C57BL/6×129/ola background were studied using the ulna axial loading model. The response to 2 days of loading for 120 cycles/day at 2 Hz was measured histomorphometrically. Phenotypic characterization of the femurs in these mice was also performed. In a separate group of animals, the expression of the remaining COX isozyme, COX-1, was assessed using real-time RT-PCR 4 h after one bout of 120 loading cycles. Results: Null mutation of the COX-2 gene resulted in a consistent femoral phenotype of reduced bone mass, altered architecture, and inferior mechanical properties. Many of these differences were nullified after adjustment for body weight. Nevertheless, body weight-corrected values showed a consistent trend of reduced mechanical properties in COX-2-/- mice. Genotype did not influence the response to mechanical loading, with no histomorphometric differences being found between COX-2+/+ and COX-2-/- mice. Real-time RT-PCR showed COX-2-/- mice to express significantly greater COX-1 expression in loaded ulnas than in loaded ulnas in COX-2 +/+ mice. There were no differences in COX-1 expression in nonloaded ulnas. Conclusions: A functional COX-2 gene was not found to be required for skeletal mechanotransduction. This is in contrast to previous pharmacological studies showing that COX-2 is critical to the response of bone to loading. Investigating a potential reason for the absence of a genotype difference in this study, we found that mice with a null mutation in the COX-2 gene possess inductive skeletal COX-1 expression.

KW - Bone adaptation

KW - Knockout

KW - Mechanical loading

KW - Prostaglandins

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