Wnt pathway genes in osteoporosis and osteoarthritis: differential expression and genetic association study

Velasco, Javier; Zarrabeitia, Marı́a T.; Prieto, Joel; Pérez‐Castrillón, José Luis; Pérez-Aguilar, M.D.; Pérez-Núñez, MI; Sañudo, Carolina; Hernandez-Elena, J.; Calvo, Ignacio; Ortiz, Fernando Rosell; González‐Macías, Jesús; Riancho, José A.

doi:10.1007/s00198-009-0931-0

Cited by 72 publications

(54 citation statements)

References 49 publications

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“…In adult life, Wnt signaling continues to play an important role in joint homeostasis. Excessive activation of this pathway is involved in regulating cartilage breakdown and bony sclerosis in osteoarthritis [57], and single-nucleotide polymorphisms (SNPs) of Wnt pathway proteins are associated with increased susceptibility to osteoarthritis [58–61]. Antagonists of the Wnt pathway are currently in clinical development for treatment of the sclerotic bony lesions of multiple myeloma [62] and osteoporosis [63], though their efficacy has not yet been tested in osteoarthritis.…”

Section: Bone Morphogenetic Proteins and The Wingless Pathway: Molecumentioning

confidence: 99%

Relationship between joint shape and the development of osteoarthritis

Baker-LePain

Lane²

2010

Current Opinion in Rheumatology

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Purpose of review To present an updated summary of the relationship between joint shape and the development of osteoarthritis, with a particular focus on osteoarthritis of the hip. Recent findings Osteoarthritis of the hip is highly heritable, with a genetic contribution estimated at 60%. Among the genes that have been linked to this disease are several that are involved in the development and maintenance of joint shape, including members of the Wingless (Wnt) and the bone morphogenetic protein (BMP) family. Several features of hip joint architecture, such as acetabular dysplasia, pistol grip deformity, wide femoral neck, altered femoral neck-shaft angle, appear to play an important role in the pathogenesis of osteoarthritis and may predate the development of osteoarthritis by decades. Summary Gene–environment interactions play a crucial role in the development of osteoarthritis. The architecture of joint shape is determined by a complex sequence spanning embryonic, childhood, and adult life and contributes to the pathogenesis of osteoarthritis.

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Section: Bone Morphogenetic Proteins and The Wingless Pathway: Molecumentioning

confidence: 99%

Relationship between joint shape and the development of osteoarthritis

Baker-LePain

Lane²

2010

Current Opinion in Rheumatology

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“…CELL CULTURE hOB cells were obtained from bone specimens extracted from knee samples otherwise discarded at the time of orthopaedic surgery in postmenopausal women, as described previously [Garcia-Moreno et al, 2002;Velasco et al, 2009] [Brandstrom et al, 1998;Hofbauer et al, 1998;Fuller et al, 2000]. For each treatment, concentration, and time, three replicate plates were used.…”

Section: Subjectsmentioning

confidence: 99%

Effect of IL‐1β, PGE₂, and TGF‐β1 on the expression of OPG and RANKL in normal and osteoporotic primary human osteoblasts

Jurado

Garcia-Giralt

Díez-Pérez

et al. 2010

J of Cellular Biochemistry

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The RANKL/RANK/OPG pathway is essential for bone remodeling regulation. Many hormones and cytokines are involved in regulating gene expression in most of the pathway components. Moreover, any deregulation of this pathway can alter bone metabolism, resulting in loss or gain of bone mass. Whether osteoblasts from osteoporotic and nonosteoporotic patients respond differently to cytokines is unknown. The aim of this study was to compare the effect of interleukin (IL)-1beta, proftaglandin E(2) (PGE(2)), and transforming growth factor-beta1 (TGF-beta1) treatments on OPG and RANKL gene expression in normal (n = 11) and osteoporotic (n = 8) primary osteoblasts. OPG and RANKL mRNA levels of primary human osteoblastic (hOB) cell cultures were assessed by real-time PCR. In all cultures, OPG mRNA increased significantly in response to IL-1beta treatment and decreased in response to TGF-beta1 whereas PGE(2) treatment had no effect. RANKL mRNA levels were significantly increased by all treatments. Differences in OPG and RANKL responses were observed between osteoporotic and nonosteoporotic hOB: in osteoporotic hOB, the OPG response to IL-1beta treatment was up to three times lower (P = 0.009), whereas that of RANKL response to TGF-beta1 was five times higher (P = 0.002) after 8 h of treatment, as compared with those in nonosteoporotic hOBs. In conclusion, osteoporotic hOB cells showed an anomalous response under cytokine stimulation, consistent with an enhanced osteoclastogenesis resulting in high levels of bone resorption.

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“…On the other hand, Wnt activity has been reported to influence cartilage 346 metabolism and may be involved in the pathogenesis of osteoarthritis 347 (Corr, 2008;Diarra et al, 2007;Lodewyckx and Lories, 2009;Luyten 348 et al, 2009 showed higher Wnt activity in osteoblasts from patients with osteoar-372 thritis than in those obtained from fracture cases (Velasco et al, 2010).…”

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confidence: 99%

Contribution of genetic and epigenetic mechanisms to Wnt pathway activity in prevalent skeletal disorders

García-Ibarbia

Delgado‐Calle

Casafont

et al. 2013

Gene

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Wnt 22 β-Catenin 23 DNA methylation 24 Fractures 25 Bone diseases 26We reported previously that the expression of Wnt-related genes is lower in osteoporotic hip fractures than in 27 osteoarthritis. We aimed to confirm those results by analyzing β-catenin levels and explored potential genetic 28 and epigenetic mechanisms involved. 29 β-Catenin gene expression and nuclear levels were analyzed by real time PCR and confocal immunofluorescence. 30 Increased nuclear β-catenin was found in osteoblasts isolated from patients with osteoarthritis (99 ± 4 31 units vs. 76 ± 12, p = 0.01, n = 10), without differences in gene transcription, which is consistent with 32 a post-translational down-regulation of β-catenin and decreased Wnt pathway activity.33 Twenty four single nucleotide polymorphisms (SNPs) of genes showing differential expression between fractures 34 and osteoarthritis (WNT4, WNT10A, WNT16 and SFRP1) were analyzed in DNA isolated from blood of 853 pa-35 tients. The genotypic frequencies were similar in both groups of patients, with no significant differences. 36 Methylation of Wnt pathway genes was analyzed in bone tissue samples (15 with fractures and 15 with osteo-37 arthritis) by interrogating a CpG-based methylation array. Six genes showed significant methylation differences 38 between both groups of patients: FZD10, TBL1X, CSNK1E, WNT8A, CSNK1A1L and SFRP4. The DNA demethylating 39 agent 5-deoxycytidine up-regulated 8 genes, including FZD10, in an osteoblast-like cell line, whereas it down-40 regulated other 16 genes. 41 In conclusion, Wnt activity is reduced in patients with hip fractures, in comparison with those with osteoarthritis. 42 It does not appear to be related to differences in the allele frequencies of the Wnt genes studied. On the other 43 hand, methylation differences between both groups could contribute to explain the differences in Wnt activity.44

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Wnt pathway genes in osteoporosis and osteoarthritis: differential expression and genetic association study

Cited by 72 publications

References 49 publications

Relationship between joint shape and the development of osteoarthritis

Relationship between joint shape and the development of osteoarthritis

Effect of IL‐1β, PGE₂, and TGF‐β1 on the expression of OPG and RANKL in normal and osteoporotic primary human osteoblasts

Contribution of genetic and epigenetic mechanisms to Wnt pathway activity in prevalent skeletal disorders

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Wnt pathway genes in osteoporosis and osteoarthritis: differential expression and genetic association study

Cited by 72 publications

References 49 publications

Relationship between joint shape and the development of osteoarthritis

Relationship between joint shape and the development of osteoarthritis

Effect of IL‐1β, PGE2, and TGF‐β1 on the expression of OPG and RANKL in normal and osteoporotic primary human osteoblasts

Contribution of genetic and epigenetic mechanisms to Wnt pathway activity in prevalent skeletal disorders

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Effect of IL‐1β, PGE₂, and TGF‐β1 on the expression of OPG and RANKL in normal and osteoporotic primary human osteoblasts