Clin Rheumatol (2014) 33:759–762 DOI 10.1007/s10067-014-2663-6
ORIGINAL ARTICLE
Wnt signaling in ankylosing spondylitis Maripat Corr
Received: 31 January 2014 / Accepted: 24 March 2014 / Published online: 13 May 2014 # Clinical Rheumatology 2014
Abstract The mechanisms that lead to bony fusion in ankylosing spondylitis (AS) are yet to be fully defined. In recent years, there have been several advances in our understanding of this complex disease. Here, the potential impact of the Wnt signaling pathway will be discussed. This pathway is involved in bone morphogenesis and homeostasis. Perturbations in the normal regulation have been implicated in abnormal bone formation (e.g., osteophytes). Levels of Wnt regulatory proteins like Dickkopf have been investigated as potential biomarkers of disease. This pathway might be involved in other aspects of this disease including T cell activation and differentiation, and in bone marrow adipogenesis. The pathways leading to the unique pathology and bony fusion in AS are complex and the Wnt pathway might play a critical contributing role.
Keywords Ankylosing spondylitis . Bone morphogenesis . Wnt signaling
The Wnt signaling pathway is essential to embryonic skeletogenesis, but also plays critical roles in homeostasis and bone health in adults. In recent years, there have been mounting data to suggest that this pathway is involved in osteoblastogenesis and regulated in part by inflammation. Aberrant regulation of this pathway has been suggested as a key element in the pathogenesis of ankylosing spondylitis (AS) [1–3].
M. Corr (*) 9500 Gilman Dr., San Diego, CA 92131-0663, USA e-mail: [email protected]
Wnt proteins and signaling To date, 19 human Wnt genes have been identified. Wnts are highly conserved lipid-modified glycoproteins. Secreted Wnt proteins can be released into the extracellular space or locally retained by binding to local heparan sulfate surface molecules to establish gradients. Wnt family members can then bind to the seven transmembrane spanning frizzled receptors. In addition, the ten frizzled receptor family members can also complex with co-receptors such as the low-density lipoprotein-related receptor (LRP) 5 or 6 [2]. Wnt proteins are not restricted to specific frizzled receptors and Wnt/ frizzled interaction can activate several different pathways including the planer cell polarity pathway, JNK signaling pathway, ROR receptor pathway, beta-catenin pathway, aPKC pathway, and RYK pathway [4]. The most widely studied pathway is the canonical pathway, which is centrally mediated through beta-catenin (reviewed in [2]). Cytoplasmic stores of beta-catenin are continually being depleted by a protein complex that phosphorylates beta-catenin and promotes proteosomal degradation. After Wnt/frizzled signaling, proteins in this complex are recruited to the membrane, allowing beta-catenin to accumulate in the cytoplasm and then translocate into the nucleus. In the nucleus, betacatenin itself is unable to bind directly to DNA and must complex with other transcription factors to enable target gene transcription. In addition to the complex intracellular regulation of beta-catenin stores, there is extracelluar regulation of this Wnt pathway. The secreted frizzled-related protein family members, Cerberus and WIF, bind as antagonists directly to extracellular Wnt. However, Dickkopf (Dkk) family members and sclerostin (SOST) bind to the LRP co-receptor to limit Wnt signal transmission to the canonical pathway. Although there are several different Wnt signaling pathways, which could play a role in the pathogenesis of AS, the comments here will be focused on the potential role of the canonical pathway (Fig. 1).
760
Clin Rheumatol (2014) 33:759–762
Fig. 1 The Wnt/beta-catenin signaling pathway. Canonical Wnt signaling occurs when a Wnt protein binds to the frizzled receptor and the lowdensity lipoprotein-related receptor (LRP5)/6 coreceptor. This activates a signaling cascade that results in stopping the complex of proteins with adenomatous polyposis coli (APC), glycogen synthase kinase-(GSK)3 beta, and Axin from tagging beta-catenin for degradation. Beta-catenin then translocates to the nucleus where it activates transcription of target
genes when complexed to other transcription factors. TNF induces the production of Wnt inhibitors: Dickkopf (DKK) and Sclerostin (SOST). DKK and SOST bind the LRP5/6 co-receptor and inhibit Wnt signaling leading to the degradation of beta-catenin in the cytoplasm. Increased Wnt signaling leads to bony proliferation and its inhibition leads to bone loss and adipocyte differentiation
Wnt in T cell phenotype and behavior
cord blood cells [7]. In already differentiated cells, the life of regulatory T cells is prolonged and anergy is induced in nonregulatory T cells [8]. The effect of Wnt signaling on the phenotype of the T cell is not only limited to direct Wnt/frizzled activation in the T cell, but also through the effect of Wnt signaling on dendritic cells (DC). DCs that receive a Wnt signal migrate to local lymph nodes and adapt a tolerogenic phenotype preferentially stimulating the development of T regulatory cells [9]. This tolerogenic signaling can be overcome by a “danger signal” such as Toll-like receptor ligation. Other investigators have shown Wnt3a stimulates TGFβ and VEGF from DCs, and Wnt5a stimulates them to produce IL-10 [10]. These DCs then promote generation of FOXP3+ regulatory T cells. It is yet unknown if Wnt signaling has any impact on directing the phenotype of the unusual CD3−CD4−CD8−IL23R+ T cells described above.
T cells are centrally implicated in acquired autoimmune diseases as opposed to autoinflammatory diseases. The activity of T cells also directly and indirectly affects bone homeostasis through cytokines and RANK activation. In AS, further T cellmediated effects were recently suggested from a newly discovered subset of murine T cells. CD3−CD4−CD8−IL23R+ T cells were isolated at the site of enthesitis in mice injected with IL-23 expressing minicircle DNA [5]. These T cells were found to produce IL-22 and IL-17. The mRNA gene expression from paws of mice overexpressing IL-23 indicated an inflammation profile; however, the gene expression pattern from mice over expressing IL-22 included a Wnt expression signature and other genes associated with bony proliferation [5]. These data suggest that it was IL-22 expressed by T cells that increased Wnt signaling and bony proliferation in the paws of this experimental mouse model of spondyloarthropathy. Wnt signaling through beta-catenin can also differentially affect T cell populations and behavior. General effects include increases in beta-catenin transcriptional target genes such as matrix metalloproteinase 3, which degrades the extracellular matrix and facilitates T cell migration [6]. Wnt signaling skews T cell differentiation toward regulatory T cells with FOXP3, and suppresses differentiation of more proinflammatory T cells such as T helper (Th)1 and Th17 cells [7, 8]. This influence on differentiation has also been described on human
Wnt antagonists as biomarkers in AS Variants in the LRP coreceptor have been linked to severe osteopenia with loss of function and in aberrant postmaturational bone accrual with gain of function in human disease states [11, 12]. These data indicated that the naturally occurring Wnt antagonists that bind LRP, namely Dkk and sclerostin could modulate bone pathology. Both Dkk and sclerostin were shown to be induced by TNF [13]. Dr. Schett
Clin Rheumatol (2014) 33:759–762
and colleagues demonstrated that blocking the activity Dkk-1 with an antibody reversed erosions in several inflammatory arthritis models in mice and altered the phenotype from bony erosion to proliferation [13]. In a separate study, this antibody blockade resulted in the fusion of the sacroiliac joints in mice that were engineered to overexpress TNF [14]. These investigators described a model whereby TNF stimulated the release of Dkk-1, which in turn suppressed Wnt signaling, and diminished osteoprotegerin and osteoblastogenesis, shifting toward increased osteoclast activity and erosion [13]. This group also demonstrated that the sera levels of human Dkk-1 fell after initiation of a TNF inhibitor in patients with rheumatoid arthritis, but not in patients with AS regardless of BASDAI score [14]. Subsequently, there have been several studies examining the utility of sclerostin and Dkk-1 as biomarkers for disease activity in AS [15–18]. To summarize, there is a difference in the results based on the technique of the assay performed. In some studies, there was a discordance in the amount of Dkk-1 protein and that capable of binding to the LRP co-receptor. In addition, the Dkk-1 in the sera of AS patients was found to be less able to suppress beta-catenin translocation to the nucleus than control sera [1], suggesting that the Dkk in AS patients might be dysfunctional. Patients in the German Spondyloarthritis Inception Cohort were found to have a higher cumulative risk of developing a syndesmophyte if they had lower levels of circulating functional Dkk-1, assayed by coating the plate with purified LRP6 rather than a capture antibody [3].
Wnt in repair Wnt signaling is quintessential for limb morphogenesis in development and in complex wound repair. In a model of limb repair, chemical inhibitors of Wnt signaling abrogated tail regeneration in zebrafish after a portion of the tail was severed, demonstrating the absolute requirement for this pathway [19]. A current paradigm for AS pathogenesis suggests that at the site of inflammation the resolution phase incorporates first a relative adipose accumulation and then bone overgrowth in the form of a syndesmophyte. Investigators have reported an increase in the fat signal in MRI imaging in the vertebrae after inflammation subsides from treatment with a TNF inhibitor [20]. Wnt signaling typically suppresses adipocyte adipogenesis [21], so at present this result is counter-intuitive as the Dkk level in these patients also declined, which should have suppressed adipogenesis. The aberrant bone formation in AS could represent an attempt to return to embryonic programming but incomplete mechanisms are in place that results in aberrant skeletal repair.
761
References 1. Daoussis D, Liossis SN, Solomou EE, Tsanaktsi A, Bounia K, Karampetsou M, Yiannopoulos G, Andonopoulos AP (2010) Evidence that Dkk-1 is dysfunctional in ankylosing spondylitis. Arthritis Rheum 62:150–158 2. Lories RJ, Corr M, Lane NE (2013) To Wnt or not to Wnt: the bone and joint health dilemma. Nat Rev Rheumatol 9:328–339 3. Heiland GR, Appel H, Poddubnyy D, Zwerina J, Hueber A, Haibel H, Baraliakos X, Listing J, Rudwaleit M, Schett G, Sieper J (2012) High level of functional Dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis. Ann Rheum Dis 71:572–574 4. McDonald SL, Silver A (2009) The opposing roles of Wnt-5a in cancer. Br J Cancer 101:209–214 5. Sherlock JP, Joyce-Shaikh B, Turner SP, Chao CC, Sathe M, Grein J, Gorman DM, Bowman EP, McClanahan TK, Yearley JH et al (2012) IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat Med 18:1069–1076 6. Wu B, Crampton SP, Hughes CC (2007) Wnt signaling induces matrix metalloproteinase expression and regulates T cell transmigration. Immunity 26:227–239 7. Muralidharan S, Hanley PJ, Liu E, Chakraborty R, Bollard C, Shpall E, Rooney C, Savoldo B, Rodgers J, Dotti G (2011) Activation of Wnt signaling arrests effector differentiation in human peripheral and cord blood-derived T lymphocytes. J Immunol 187:5221–5232 8. Ding Y, Shen S, Lino AC, Curotto de Lafaille MA, Lafaille JJ (2008) Beta-catenin stabilization extends regulatory T cell survival and induces anergy in nonregulatory T cells. Nat Med 14:162–169 9. Manicassamy S, Reizis B, Ravindran R, Nakaya H, SalazarGonzalez RM, Wang YC, Pulendran B (2010) Activation of betacatenin in dendritic cells regulates immunity versus tolerance in the intestine. Science 329:849–853 10. Oderup C, LaJevic M, Butcher EC (2013) Canonical and noncanonical Wnt proteins program dendritic cell responses for tolerance. J Immunol 190:6126–6134 11. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D et al (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513–523 12. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346:1513–1521 13. Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, Korb A, Smolen J, Hoffmann M, Scheinecker C et al (2007) Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13: 156–163 14. Uderhardt S, Diarra D, Katzenbeisser J, David JP, Zwerina J, Richards W, Kronke G, Schett G (2010) Blockade of Dickkopf (DKK)-1 induces fusion of sacroiliac joints. Ann Rheum Dis 69:592–597 15. Kwon SR, Lim MJ, Suh CH, Park SG, Hong YS, Yoon BY, Kim HA, Choi HJ, Park W (2012) Dickkopf-1 level is lower in patients with ankylosing spondylitis than in healthy people and is not influenced by anti-tumor necrosis factor therapy. Rheumatol Int 32:2523–2527 16. Saad CG, Ribeiro AC, Moraes JC, Takayama L, Goncalves CR, Rodrigues MB, de Oliveira RM, Silva CA, Bonfa E, Pereira RM (2012) Low sclerostin levels: a predictive marker of persistent inflammation in ankylosing spondylitis during anti-tumor necrosis factor therapy? Arthritis Res Ther 14:R216 17. Taylan A, Sari I, Akinci B, Bilge S, Kozaci D, Akar S, Colak A, Yalcin H, Gunay N, Akkoc N (2012) Biomarkers and cytokines of bone turnover: extensive evaluation in a cohort of patients with ankylosing spondylitis. BMC Musculoskelet Disord 13:191 18. Appel H, Ruiz-Heiland G, Listing J, Zwerina J, Herrmann M, Mueller R, Haibel H, Baraliakos X, Hempfing A, Rudwaleit M
762 et al (2009) Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis Rheum 60:3257–3262 19. Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, Charlat O, Wiellette E, Zhang Y, Wiessner S et al (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461:614–620
Clin Rheumatol (2014) 33:759–762 20. Hu Z, Xu M, Li Q, Lin Z, Liao Z, Cao S, Wei Q, Zhang YL, Li T, Jin O et al (2012) Adalimumab significantly reduces inflammation and serum DKK-1 level but increases fatty deposition in lumbar spine in active ankylosing spondylitis. Int J Rheum Dis 15:358–365 21. Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, MacDougald OA (2000) Inhibition of adipogenesis by Wnt signaling. Science 289:950–953
ORIGINAL ARTICLE
Wnt signaling in ankylosing spondylitis Maripat Corr
Received: 31 January 2014 / Accepted: 24 March 2014 / Published online: 13 May 2014 # Clinical Rheumatology 2014
Abstract The mechanisms that lead to bony fusion in ankylosing spondylitis (AS) are yet to be fully defined. In recent years, there have been several advances in our understanding of this complex disease. Here, the potential impact of the Wnt signaling pathway will be discussed. This pathway is involved in bone morphogenesis and homeostasis. Perturbations in the normal regulation have been implicated in abnormal bone formation (e.g., osteophytes). Levels of Wnt regulatory proteins like Dickkopf have been investigated as potential biomarkers of disease. This pathway might be involved in other aspects of this disease including T cell activation and differentiation, and in bone marrow adipogenesis. The pathways leading to the unique pathology and bony fusion in AS are complex and the Wnt pathway might play a critical contributing role.
Keywords Ankylosing spondylitis . Bone morphogenesis . Wnt signaling
The Wnt signaling pathway is essential to embryonic skeletogenesis, but also plays critical roles in homeostasis and bone health in adults. In recent years, there have been mounting data to suggest that this pathway is involved in osteoblastogenesis and regulated in part by inflammation. Aberrant regulation of this pathway has been suggested as a key element in the pathogenesis of ankylosing spondylitis (AS) [1–3].
M. Corr (*) 9500 Gilman Dr., San Diego, CA 92131-0663, USA e-mail: [email protected]
Wnt proteins and signaling To date, 19 human Wnt genes have been identified. Wnts are highly conserved lipid-modified glycoproteins. Secreted Wnt proteins can be released into the extracellular space or locally retained by binding to local heparan sulfate surface molecules to establish gradients. Wnt family members can then bind to the seven transmembrane spanning frizzled receptors. In addition, the ten frizzled receptor family members can also complex with co-receptors such as the low-density lipoprotein-related receptor (LRP) 5 or 6 [2]. Wnt proteins are not restricted to specific frizzled receptors and Wnt/ frizzled interaction can activate several different pathways including the planer cell polarity pathway, JNK signaling pathway, ROR receptor pathway, beta-catenin pathway, aPKC pathway, and RYK pathway [4]. The most widely studied pathway is the canonical pathway, which is centrally mediated through beta-catenin (reviewed in [2]). Cytoplasmic stores of beta-catenin are continually being depleted by a protein complex that phosphorylates beta-catenin and promotes proteosomal degradation. After Wnt/frizzled signaling, proteins in this complex are recruited to the membrane, allowing beta-catenin to accumulate in the cytoplasm and then translocate into the nucleus. In the nucleus, betacatenin itself is unable to bind directly to DNA and must complex with other transcription factors to enable target gene transcription. In addition to the complex intracellular regulation of beta-catenin stores, there is extracelluar regulation of this Wnt pathway. The secreted frizzled-related protein family members, Cerberus and WIF, bind as antagonists directly to extracellular Wnt. However, Dickkopf (Dkk) family members and sclerostin (SOST) bind to the LRP co-receptor to limit Wnt signal transmission to the canonical pathway. Although there are several different Wnt signaling pathways, which could play a role in the pathogenesis of AS, the comments here will be focused on the potential role of the canonical pathway (Fig. 1).
760
Clin Rheumatol (2014) 33:759–762
Fig. 1 The Wnt/beta-catenin signaling pathway. Canonical Wnt signaling occurs when a Wnt protein binds to the frizzled receptor and the lowdensity lipoprotein-related receptor (LRP5)/6 coreceptor. This activates a signaling cascade that results in stopping the complex of proteins with adenomatous polyposis coli (APC), glycogen synthase kinase-(GSK)3 beta, and Axin from tagging beta-catenin for degradation. Beta-catenin then translocates to the nucleus where it activates transcription of target
genes when complexed to other transcription factors. TNF induces the production of Wnt inhibitors: Dickkopf (DKK) and Sclerostin (SOST). DKK and SOST bind the LRP5/6 co-receptor and inhibit Wnt signaling leading to the degradation of beta-catenin in the cytoplasm. Increased Wnt signaling leads to bony proliferation and its inhibition leads to bone loss and adipocyte differentiation
Wnt in T cell phenotype and behavior
cord blood cells [7]. In already differentiated cells, the life of regulatory T cells is prolonged and anergy is induced in nonregulatory T cells [8]. The effect of Wnt signaling on the phenotype of the T cell is not only limited to direct Wnt/frizzled activation in the T cell, but also through the effect of Wnt signaling on dendritic cells (DC). DCs that receive a Wnt signal migrate to local lymph nodes and adapt a tolerogenic phenotype preferentially stimulating the development of T regulatory cells [9]. This tolerogenic signaling can be overcome by a “danger signal” such as Toll-like receptor ligation. Other investigators have shown Wnt3a stimulates TGFβ and VEGF from DCs, and Wnt5a stimulates them to produce IL-10 [10]. These DCs then promote generation of FOXP3+ regulatory T cells. It is yet unknown if Wnt signaling has any impact on directing the phenotype of the unusual CD3−CD4−CD8−IL23R+ T cells described above.
T cells are centrally implicated in acquired autoimmune diseases as opposed to autoinflammatory diseases. The activity of T cells also directly and indirectly affects bone homeostasis through cytokines and RANK activation. In AS, further T cellmediated effects were recently suggested from a newly discovered subset of murine T cells. CD3−CD4−CD8−IL23R+ T cells were isolated at the site of enthesitis in mice injected with IL-23 expressing minicircle DNA [5]. These T cells were found to produce IL-22 and IL-17. The mRNA gene expression from paws of mice overexpressing IL-23 indicated an inflammation profile; however, the gene expression pattern from mice over expressing IL-22 included a Wnt expression signature and other genes associated with bony proliferation [5]. These data suggest that it was IL-22 expressed by T cells that increased Wnt signaling and bony proliferation in the paws of this experimental mouse model of spondyloarthropathy. Wnt signaling through beta-catenin can also differentially affect T cell populations and behavior. General effects include increases in beta-catenin transcriptional target genes such as matrix metalloproteinase 3, which degrades the extracellular matrix and facilitates T cell migration [6]. Wnt signaling skews T cell differentiation toward regulatory T cells with FOXP3, and suppresses differentiation of more proinflammatory T cells such as T helper (Th)1 and Th17 cells [7, 8]. This influence on differentiation has also been described on human
Wnt antagonists as biomarkers in AS Variants in the LRP coreceptor have been linked to severe osteopenia with loss of function and in aberrant postmaturational bone accrual with gain of function in human disease states [11, 12]. These data indicated that the naturally occurring Wnt antagonists that bind LRP, namely Dkk and sclerostin could modulate bone pathology. Both Dkk and sclerostin were shown to be induced by TNF [13]. Dr. Schett
Clin Rheumatol (2014) 33:759–762
and colleagues demonstrated that blocking the activity Dkk-1 with an antibody reversed erosions in several inflammatory arthritis models in mice and altered the phenotype from bony erosion to proliferation [13]. In a separate study, this antibody blockade resulted in the fusion of the sacroiliac joints in mice that were engineered to overexpress TNF [14]. These investigators described a model whereby TNF stimulated the release of Dkk-1, which in turn suppressed Wnt signaling, and diminished osteoprotegerin and osteoblastogenesis, shifting toward increased osteoclast activity and erosion [13]. This group also demonstrated that the sera levels of human Dkk-1 fell after initiation of a TNF inhibitor in patients with rheumatoid arthritis, but not in patients with AS regardless of BASDAI score [14]. Subsequently, there have been several studies examining the utility of sclerostin and Dkk-1 as biomarkers for disease activity in AS [15–18]. To summarize, there is a difference in the results based on the technique of the assay performed. In some studies, there was a discordance in the amount of Dkk-1 protein and that capable of binding to the LRP co-receptor. In addition, the Dkk-1 in the sera of AS patients was found to be less able to suppress beta-catenin translocation to the nucleus than control sera [1], suggesting that the Dkk in AS patients might be dysfunctional. Patients in the German Spondyloarthritis Inception Cohort were found to have a higher cumulative risk of developing a syndesmophyte if they had lower levels of circulating functional Dkk-1, assayed by coating the plate with purified LRP6 rather than a capture antibody [3].
Wnt in repair Wnt signaling is quintessential for limb morphogenesis in development and in complex wound repair. In a model of limb repair, chemical inhibitors of Wnt signaling abrogated tail regeneration in zebrafish after a portion of the tail was severed, demonstrating the absolute requirement for this pathway [19]. A current paradigm for AS pathogenesis suggests that at the site of inflammation the resolution phase incorporates first a relative adipose accumulation and then bone overgrowth in the form of a syndesmophyte. Investigators have reported an increase in the fat signal in MRI imaging in the vertebrae after inflammation subsides from treatment with a TNF inhibitor [20]. Wnt signaling typically suppresses adipocyte adipogenesis [21], so at present this result is counter-intuitive as the Dkk level in these patients also declined, which should have suppressed adipogenesis. The aberrant bone formation in AS could represent an attempt to return to embryonic programming but incomplete mechanisms are in place that results in aberrant skeletal repair.
761
References 1. Daoussis D, Liossis SN, Solomou EE, Tsanaktsi A, Bounia K, Karampetsou M, Yiannopoulos G, Andonopoulos AP (2010) Evidence that Dkk-1 is dysfunctional in ankylosing spondylitis. Arthritis Rheum 62:150–158 2. Lories RJ, Corr M, Lane NE (2013) To Wnt or not to Wnt: the bone and joint health dilemma. Nat Rev Rheumatol 9:328–339 3. Heiland GR, Appel H, Poddubnyy D, Zwerina J, Hueber A, Haibel H, Baraliakos X, Listing J, Rudwaleit M, Schett G, Sieper J (2012) High level of functional Dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis. Ann Rheum Dis 71:572–574 4. McDonald SL, Silver A (2009) The opposing roles of Wnt-5a in cancer. Br J Cancer 101:209–214 5. Sherlock JP, Joyce-Shaikh B, Turner SP, Chao CC, Sathe M, Grein J, Gorman DM, Bowman EP, McClanahan TK, Yearley JH et al (2012) IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat Med 18:1069–1076 6. Wu B, Crampton SP, Hughes CC (2007) Wnt signaling induces matrix metalloproteinase expression and regulates T cell transmigration. Immunity 26:227–239 7. Muralidharan S, Hanley PJ, Liu E, Chakraborty R, Bollard C, Shpall E, Rooney C, Savoldo B, Rodgers J, Dotti G (2011) Activation of Wnt signaling arrests effector differentiation in human peripheral and cord blood-derived T lymphocytes. J Immunol 187:5221–5232 8. Ding Y, Shen S, Lino AC, Curotto de Lafaille MA, Lafaille JJ (2008) Beta-catenin stabilization extends regulatory T cell survival and induces anergy in nonregulatory T cells. Nat Med 14:162–169 9. Manicassamy S, Reizis B, Ravindran R, Nakaya H, SalazarGonzalez RM, Wang YC, Pulendran B (2010) Activation of betacatenin in dendritic cells regulates immunity versus tolerance in the intestine. Science 329:849–853 10. Oderup C, LaJevic M, Butcher EC (2013) Canonical and noncanonical Wnt proteins program dendritic cell responses for tolerance. J Immunol 190:6126–6134 11. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D et al (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513–523 12. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346:1513–1521 13. Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, Korb A, Smolen J, Hoffmann M, Scheinecker C et al (2007) Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13: 156–163 14. Uderhardt S, Diarra D, Katzenbeisser J, David JP, Zwerina J, Richards W, Kronke G, Schett G (2010) Blockade of Dickkopf (DKK)-1 induces fusion of sacroiliac joints. Ann Rheum Dis 69:592–597 15. Kwon SR, Lim MJ, Suh CH, Park SG, Hong YS, Yoon BY, Kim HA, Choi HJ, Park W (2012) Dickkopf-1 level is lower in patients with ankylosing spondylitis than in healthy people and is not influenced by anti-tumor necrosis factor therapy. Rheumatol Int 32:2523–2527 16. Saad CG, Ribeiro AC, Moraes JC, Takayama L, Goncalves CR, Rodrigues MB, de Oliveira RM, Silva CA, Bonfa E, Pereira RM (2012) Low sclerostin levels: a predictive marker of persistent inflammation in ankylosing spondylitis during anti-tumor necrosis factor therapy? Arthritis Res Ther 14:R216 17. Taylan A, Sari I, Akinci B, Bilge S, Kozaci D, Akar S, Colak A, Yalcin H, Gunay N, Akkoc N (2012) Biomarkers and cytokines of bone turnover: extensive evaluation in a cohort of patients with ankylosing spondylitis. BMC Musculoskelet Disord 13:191 18. Appel H, Ruiz-Heiland G, Listing J, Zwerina J, Herrmann M, Mueller R, Haibel H, Baraliakos X, Hempfing A, Rudwaleit M
762 et al (2009) Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis Rheum 60:3257–3262 19. Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, Charlat O, Wiellette E, Zhang Y, Wiessner S et al (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461:614–620
Clin Rheumatol (2014) 33:759–762 20. Hu Z, Xu M, Li Q, Lin Z, Liao Z, Cao S, Wei Q, Zhang YL, Li T, Jin O et al (2012) Adalimumab significantly reduces inflammation and serum DKK-1 level but increases fatty deposition in lumbar spine in active ankylosing spondylitis. Int J Rheum Dis 15:358–365 21. Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, MacDougald OA (2000) Inhibition of adipogenesis by Wnt signaling. Science 289:950–953
