Wnt pathway genes in osteoporosis and osteoarthritis: differential expression and genetic association study.
In comparison with hip fractures, increased expression of genes in the Wnt pathway and increased Wnt activity were found in bone samples and osteoblast cultures from patients with osteoarthritis, suggesting the involvement of this pathway in subchondral bone changes. No consistent differences were found in the genetic association study.


BACKGROUND
This study aims to explore the allelic variations and expression of Wnt pathway genes in patients with osteoporosis and osteoarthritis.


METHODS
The expression of 86 genes was studied in bone samples and osteoblast primary cultures from patients with hip fractures and hip or knee osteoarthritis. The Wnt-related activity was assessed by measuring AXIN2 and in transfection experiments. Fifty-five SNPs of the LRP5, LRP6, FRZB, and SOST genes were analyzed in 1,128 patients.


RESULTS
Several genes were differentially expressed in bone tissue, with the lowest values usually found in hip fracture and the highest in knee osteoarthritis. Overall, seven genes were consistently upregulated both in tissue samples and in cell cultures from patients with knee osteoarthritis (BCL9, FZD5, DVL2, EP300, FRZB, LRP5, and TCF7L1). The increased expression of AXIN2 and experiments of transient transfection of osteoblasts with the TOP-Flash construct confirmed the activation of Wnt signaling. Three SNPs of the LRP5 gene and one in the LRP6 gene showed marginally significant differences in allelic frequencies across the patient groups, but they did not resist multiple-test adjustment.


CONCLUSIONS
Genes in the Wnt pathway are upregulated in the osteoarthritic bone, suggesting their involvement not only in cartilage distortion but also in subchondral bone changes.
Department of Internal Medicine, Hospital U M Valdecilla, IFIMAV, RETICEF, University of Cantabria, Santander, Spain.
J
J
Velasco
M T
MT
Zarrabeitia
J R
JR
Prieto
J L
JL
Perez-Castrillon
M D
MD
Perez-Aguilar
M I
MI
Perez-Nuñez
C
C
Sañudo
J
J
Hernandez-Elena
I
I
Calvo
F
F
Ortiz
J
J
Gonzalez-Macias
J A
JA
Riancho
D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006620:Hip Fractures / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D010003:Osteoarthritis / Q000235:genetics* / Q000378:metabolism; D015207:Osteoarthritis, Hip / Q000235:genetics / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism; D010024:Osteoporosis / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism
D051153:Wnt Proteins