Wnt5a is expressed in spondyloarthritis and exerts opposite effects on enthesis and bone in murine organ and cell cultures

Bougault, Carole; Briolay, Anne; Boutet, Marie-Astrid; Pilet, Paul; Delplace, Séverine; Goff, Benoît Le; Guicheux, Jérôme; Blanchard, Frédéric; Magne, David

doi:10.1016/j.trsl.2015.06.010

Cited by 13 publications

(13 citation statements)

References 48 publications

(80 reference statements)

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“…WNT‐5a inhibits bone formation by enhancing RANKL‐induced osteoclastogenesis and its up‐regulated expression may also enhance the expression of inflammatory‐related genes and intracellular reactive oxygen species through a novel NF‐κB‐dependent regulation . Increased expression of WNT‐5a has been found associated with inflammatory diseases such as atherosclerosis, rheumatoid arthritis, periodontal disease, chronic apical periodontitis, spondyloarthritis as well as in patients with polycystic ovary revealing its potential involvement in the regulation of inflammation . An association between Wnt5a gene and severe chronic periodontal disease was also reported in a genome‐wide association study by Divaris et al…”

Section: Introductionmentioning

confidence: 87%

“…17 Increased expression of WNT-5a has been found associated with inflammatory diseases such as atherosclerosis, rheumatoid arthritis, periodontal disease, chronic apical periodontitis, spondyloarthritis as well as in patients with polycystic ovary revealing its potential involvement in the regulation of inflammation. [18][19][20][21] An association between Wnt5a gene and severe chronic periodontal disease was also reported in a genome-wide association study by Divaris et al 22 Tumor necrosis factor (TNF)-α is a well-known pro-inflammatory cytokine that plays an important role in periodontal disease.…”

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confidence: 94%

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Sclerostin and WNT‐5a gingival protein levels in chronic periodontitis and health

Chatzopoulos

Mansky

Lunos

et al. 2019

J of Periodontal Research

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Background and Objective Wnt signaling pathways regulate osteoblast differentiation and bone formation and are associated with inflammatory responses driven by innate and adaptive immunity via the NF‐κB pathway. The aim of this study was to compare the levels of sclerostin (SOST), WNT‐5a, and TNF‐α between chronic periodontitis and periodontally healthy sites and determine their value as diagnostic markers of chronic periodontitis. Material and Methods In a cross‐sectional assessment 25 chronic periodontitis cases and 25 periodontally healthy controls were selected upon clinical and radiographic periodontal evaluation. Gingival crevicular fluid (GCF) was collected cross‐sectionally from diseased and healthy sites in periodontitis patients and from healthy sites in each control subject. In a subgroup analysis, ten patients with generalized moderate and severe chronic periodontitis and ten generalized periodontally healthy individuals were included. The protein levels of SOST, WNT‐5a, and TNF‐α in GCF were measured by sandwich ELISA. The Shapiro‐Wilk test was utilized to assess the normality of the distribution and non‐parametric comparisons were performed. Results The protein levels of SOST were significantly higher in the generalized moderate and severe chronic periodontitis subgroup when compared to the generalized healthy (P = 0.002), while the WNT‐5a and TNF‐α GCF total amounts were similar (P > 0.05). Diseased sites in the periodontitis patients exhibited significantly higher total protein levels of WNT‐5a than in healthy sites (P = 0.017), whereas no differences were detected for SOST and TNF‐α (P > 0.05). The total protein levels of SOST, WNT‐5a, and TNF‐α in GCF were similar in periodontitis and non‐periodontitis patients (P > 0.05). Conclusions Sclerostin and WNT‐5a gingival protein levels demonstrated a high diagnostic value for generalized moderate and severe chronic periodontitis, while a low accuracy was detected for localized chronic periodontitis.

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Section: Introductionmentioning

confidence: 87%

mentioning

confidence: 94%

Sclerostin and WNT‐5a gingival protein levels in chronic periodontitis and health

Chatzopoulos

Mansky

Lunos

et al. 2019

J of Periodontal Research

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“…Synovial fluids (SFs) were obtained during an arthrocentesis as described . Arthrocentesis was performed in case of patients subjected to an acute flare of the disease.…”

Section: Methodsmentioning

confidence: 99%

“…RNA extraction and reverse transcription were performed as described . Real‐time PCR was completed using iTaq Universal SYBR green supermix on the CFX96 Touch™ Real‐Time PCR detection system (Bio‐Rad).…”

Section: Methodsmentioning

confidence: 99%

Cytokine-Induced and Stretch-Induced Sphingosine 1-Phosphate Production by Enthesis Cells Could Favor Abnormal Ossification in Spondyloarthritis

Jamal

Briolay

Mébarek

et al. 2019

Journal of Bone and Mineral Research

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Spondyloarthritis (SpA) is a common rheumatic disease characterized by enthesis inflammation (enthesitis) and ectopic ossification (enthesophytes). The current pathogenesis model suggests that inflammation and mechanical stress are both strongly involved in SpA pathophysiology. We have previously observed that the levels of sphingosine 1‐phosphate (S1P), a bone anabolic molecule, were particularly high in SpA patients' serum compared to healthy donors. Therefore, we wondered how this deregulation was related to SpA molecular mechanisms. Mouse primary osteoblasts, chondrocytes, and tenocytes were used as cell culture models. The sphingosine kinase 1 (Sphk1) gene expression and S1P secretion were significantly enhanced by cyclic stretch in osteoblasts and chondrocytes. Further, TNF‐α and IL‐17, cytokines implicated in enthesitis, increased Sphk1 mRNA in chondrocytes in an additive manner when combined to stretch. The immunochemistry on mouse ankles showed that sphingosine kinase 1 (SK1) was localized in some chondrocytes; the addition of a pro‐inflammatory cocktail augmented Sphk1 expression in cultured ankles. Subsequently, fingolimod was used to block S1P metabolism in cell cultures. It inhibited S1P receptors (S1PRs) signaling and SK1 and SK2 activity in both osteoblasts and chondrocytes. Fingolimod also reduced S1PR‐induced activation by SpA patients' synovial fluid (SF), demonstrating that the stimulation of chondrocytes by SFs from SpA patients involves S1P. In addition, when the osteogenic culture medium was supplemented with fingolimod, alkaline phosphatase activity, matrix mineralization, and bone formation markers were significantly reduced in osteoblasts and hypertrophic chondrocytes. Osteogenic differentiation was accompanied by an increase in S1prs mRNA, especially S1P1/3, but their contribution to S1P‐impact on mineralization seemed limited. Our results suggest that S1P might be overproduced in SpA enthesis in response to cytokines and mechanical stress, most likely by chondrocytes. Moreover, S1P could locally favor the abnormal ossification of the enthesis; therefore, blocking the S1P metabolic pathway could be a potential therapeutic approach for the treatment of SpA. © 2019 American Society for Bone and Mineral Research.

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“…We also found one possible mechanism underlying the increase of ALP expression in Anxa5 deletion by upregulation of BMP4, which is known to activate ALP in various tissues . Downregulation of Wnt5a in primary chondrocytes may also be responsible because it has been reported to decrease ALP expression in cultured chondrocytes, enthesis explant, and periodontal ligament (PDL) cells . The increased Bmp4 and decreased Wnt5a levels may be due to the enhanced chondrogenic differentiation.…”

Section: Discussionmentioning

confidence: 68%

Annexin A5 Involvement in Bone Overgrowth at the Enthesis

Shimada

Ideno

Arai

et al. 2018

Journal of Bone and Mineral Research

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Little is known about the molecular mechanisms of enthesis formation in mature animals. Here, we report that annexin A5 (Anxa5) plays a critical role in the regulation of bone ridge outgrowth at the entheses. We found that Anxa5 is highly expressed in the entheses of postnatal and adult mice. In Anxa5-deficient (Anxa5 ) mice, the sizes of bone ridge outgrowths at the entheses of the tibias and femur were increased after age 7 weeks. Bone overgrowth was not observed at the fibrous enthesis where the fibrocartilage layer does not exist. More ALP-expressing cells were observed in the fibrocartilage layer in Anxa5 mice than in wild-type (WT) mice. Calcein and Alizarin Red double labeling revealed more mineralized areas in Anxa5 mice than WT mice. To examine the effects of mechanical forces, we performed tenotomy in which transmission of contractile forces by the tibial muscle was impaired by surgical muscle release. In tenotomized mice, bone overgrowth at the enthesis in Anxa5 mice was decreased to a level comparable to that in WT mice at 8 weeks after the operation. The tail-suspended mice also showed a decrease in bone overgrowth to similar levels in Anxa5 and WT mice at 8 weeks after hindlimb unloading. These results suggest that bone overgrowth at the enthesis requires mechanical forces. We further examined effects of Anxa5 gene knockdown (KD) in primary cultures of osteoblasts, chondrocytes, and tenocytes in vitro. Anxa5 KD increased ALP expression in tenocytes and chondrocytes but not in osteoblasts, suggesting that increased ALP activity in the fibrocartilaginous tissue in Anxa5 mice is directly caused by Anxa5 deletion in tenocytes or fibrocartilage cells. These data indicate that Anxa5 prevents bone overgrowth at the enthesis, whose formation is mediated through mechanical forces and modulating expression of mineralization regulators. © 2018 American Society for Bone and Mineral Research.

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Wnt5a is expressed in spondyloarthritis and exerts opposite effects on enthesis and bone in murine organ and cell cultures

Cited by 13 publications

References 48 publications

Sclerostin and WNT‐5a gingival protein levels in chronic periodontitis and health

Sclerostin and WNT‐5a gingival protein levels in chronic periodontitis and health

Cytokine-Induced and Stretch-Induced Sphingosine 1-Phosphate Production by Enthesis Cells Could Favor Abnormal Ossification in Spondyloarthritis

Annexin A5 Involvement in Bone Overgrowth at the Enthesis

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