Thiazolidinediones increase the wingless-type MMTV integration site family (WNT) inhibitor Dickkopf-1 in adipocytes: a link with osteogenesis
Dickkopf-1 (DKK1) is a secreted inhibitor of canonical wingless-type MMTV integration site family (WNT) signalling; the key pathway for cell fate and development. Inhibition of WNT signalling by DKK1 in precursor cells promotes adipogenesis and inhibits osteogenesis. Previous studies have shown that treatment of type 2 diabetic patients with thiazolidinediones (TZDs) reduces bone density and increases risk of bone fractures, while body fat is increased.
We examined the effect of TZDs on secretion and DKK1 levels in pre-adipocytes and mature adipose cells and also measured circulating DKK1 levels in 11 patients with type 2 diabetes before and after treatment with the TZD rosiglitazone for 90 days.
TZDs added in vitro rapidly increased DKK1 protein levels and secretion in both fully differentiated adipose cells and pre-adipocytes undergoing differentiation. In parallel, β-catenin levels, a marker of canonical WNT signalling, were reduced. Serum levels of DKK1 were also increased in several of the patients with type 2 diabetes after treatment with rosiglitazone for 90 days.
These results provide a novel mechanism whereby peroxisome proliferator-activated receptor-γ activation can terminate WNT signalling and promote adipogenesis. Furthermore, they provide an explanation for why TZD treatment can lead to reduced bone formation and increased risk of fractures, since inhibited WNT signalling in progenitor cells promotes adipogenesis while osteogenesis is reduced.
- Yang X, Smith U (2007) Adipose tissue distribution and risk of metabolic disease: does thiazolidinedione-induced adipose tissue redistribution provide a clue to the answer? Diabetologia 50:1127–1139 CrossRef
- Grey A, Bolland M, Gamble G et al (2007) The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone decreases bone formation and bone mineral density in healthy postmenopausal women: a randomized, controlled trial. J Clin Endocrinol Metab 92:1305–1310 CrossRef
- Kahn SE, Zinman B, Lachin JM et al (2008) Rosiglitazone-associated fractures in type 2 diabetes: an analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care 31:845–851 CrossRef
- Schwartz AV, Sellmeyer DE, Vittinghoff E et al (2006) Thiazolidinedione use and bone loss in older diabetic adults. J Clin Endocrinol Metab 91:3349–3354 CrossRef
- Benvenuti S, Cellai I, Luciani P et al (2007) Rosiglitazone stimulates adipogenesis and decreases osteoblastogenesis in human mesenchymal stem cells. J Endocrinol Invest 30:RC26–RC30
- Shockley KR, Lazarenko OP, Czernik PJ, Rosen CJ, Churchill GA, Lecka-Czernik B (2009) PPARgamma2 nuclear receptor controls multiple regulatory pathways of osteoblast differentiation from marrow mesenchymal stem cells. J Cell Biochem 106:232–246 CrossRef
- Gregory CA, Singh H, Perry AS, Prockop DJ (2003) The Wnt signaling inhibitor dickkopf-1 is required for reentry into the cell cycle of human adult stem cells from bone marrow. J Biol Chem 278:28067–28078 CrossRef
- Diarra D, Stolina M, Polzer K et al (2007) Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13:156–163 CrossRef
- Yaccoby S, Ling W, Zhan F, Walker R, Barlogie B, Shaughnessy JD Jr (2007) Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood 109:2106–2111 CrossRef
- Politou MC, Heath DJ, Rahemtulla A et al (2006) Serum concentrations of Dickkopf-1 protein are increased in patients with multiple myeloma and reduced after autologous stem cell transplantation. Int J Cancer 119:1728–1731 CrossRef
- Kennell JA, MacDougald OA (2005) Wnt signaling inhibits adipogenesis through beta-catenin-dependent and -independent mechanisms. J Biol Chem 280:24004–24010 CrossRef
- Gustafson B, Smith U (2006) Cytokines promote Wnt signaling and inflammation and impair the normal differentiation and lipid accumulation in 3T3–L1 preadipocytes. J Biol Chem 281:9507–9516 CrossRef
- Isakson P, Hammarstedt A, Gustafson B, Smith U (2009) Impaired preadipocyte differentiation in human abdominal obesity: role of Wnt, tumor necrosis factor-alpha, and inflammation. Diabetes 58:1550–1557 CrossRef
- Mao B, Wu W, Li Y et al (2001) LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature 411:321–325 CrossRef
- Lee N, Smolarz AJ, Olson S et al (2007) A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies. Br J Cancer 97:1552–1559 CrossRef
- Gimble JM, Zvonic S, Floyd ZE, Kassem M, Nuttall ME (2006) Playing with bone and fat. J Cell Biochem 98:251–266 CrossRef
- Thiazolidinediones increase the wingless-type MMTV integration site family (WNT) inhibitor Dickkopf-1 in adipocytes: a link with osteogenesis
Volume 53, Issue 3 , pp 536-540
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- WNT signalling
- Industry Sectors
- Author Affiliations
- 1. The Lundberg Laboratory for Diabetes Research, Center of Excellence for Metabolic and Cardiovascular Research, Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Blå Stråket 3, 413 45, Gothenburg, Sweden