Knochen wird durch die koordinierte Aktivität von knochenresorbierenden Osteoklasten sowie von Osteoblasten, die neue Knochenmatrix produzieren, kontinuierlich umgebaut. Ein gestörtes Gleichgewicht zwischen beiden Zelltypen stellt ein Leitmotiv vieler metabolischer Knochenerkrankungen dar. Hierbei fällt dem Wnt-Signalweg eine zentrale Bedeutung zu. Dieser fördert die Osteoblastogenese und wird durch die Wnt-Antagonisten Dickkopf-1 (DKK-1) und Sklerostin feinreguliert, da sie eine hemmende Wirkung auf die Osteoblasten-differenzierung entfalten. Beide Proteine sind zellbiologisch gut charakterisiert und lassen sich auch beim Menschen mithilfe sensitiver Assays nachweisen und als Biomarker bestimmen. Sowohl DKK-1 und Sklerostin werden in aktuellen präklinischen und klinischen Studien als therapeutische Ansatzpunkte für Erkrankungen des Knochens diskutiert, bei denen es zu einem Verlust von Knochengewebe und einem erhöhten Frakturrisiko kommt.
Summary
Bone undergoes continuous remodeling by the tightly coordinated activities of both bone resorbing osteoclasts as well as osteoblasts which produce new mineralized bone matrix. An imbalance of these cell types is a hallmark of numerous metabolic bone disorders. The Wnt pathway plays a key role in bone remodeling by promoting the differentiation of osteoblasts. Dickkopf-1 (DKK-1) and Sclerostin represent two potent inhibitors of the Wnt pathway thereby mediating a finetuning of osteoblastogenesis. The biological function of these proteins is well characterized and both are detectable as biomarkers in humans by sensitive assays. Current preclinical and clinical studies point to the potential therapeutic benefit by targeting DKK-1 and Sclerostin in bone disorders that are accompanied by the loss of bone mass and an increased fracture risk.
6
Kato M,
Patel MS,
Levasseur R.
et al.
Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol 2002; 157: 303-314.
7
Daoussis D,
Andonopoulos AP.
The emerging role of Dickkopf-1 in bone biology: is it the main switch controlling bone and joint remodeling?. Semin Arthritis Rheum 2011; 41: 170-177.
12
Li X,
Ominsky MS,
Niu Q-T.
et al.
Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 2008; 23: 860-869.
14
Van Bezooijen RL,
Ten Dijke P,
Papapoulos SE,
Löwik CWGM.
SOST/sclerostin, an osteocyte-derived negative regulator of bone formation. Cytokine Growth Factor Rev 2005; 16: 319-327.
15
Sutherland MK,
Geoghegan JC,
Yu C.
et al.
Sclerostin promotes the apoptosis of human osteoblastic cells: A novel regulation of bone formation. Bone 2004; 35: 828-835.
16
Robling AG,
Niziolek PJ,
Baldridge LA.
et al.
Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem 2008; 283: 5866-5875.
19
Neer RM,
Arnaud CD,
Zanchetta JR.
et al.
Effect of Parathyroid Hormone 1–34) on Fractures and Bone Mineral Density in Postmenopausal Women With Osteoporosis. N Engl J Med 2001; 344: 1434-1441.
24
Gaudio A,
Pennisi P,
Bratengeier C.
et al.
Increased sclerostin serum levels associated with bone formation and resorption markers in patients with immobilization-induced bone loss. J Clin Endocrinol Metab 2010; 95: 2248-2253.
26
Glantschnig H,
Fisher JE,
Wesolowski G.
et al.
M-CSF, TNFalpha and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase. Cell Death Differ 2003; 10: 1165-1177.
27
Hadji P,
Ziller M,
Maskow C.
et al.
The influence of chemotherapy on bone mineral density, quantitative ultrasonometry and bone turnover in pre-menopausal women with breast cancer. Eur J Cancer 2009; 45: 3205-3212.
28
Hadji P,
Aapro MS,
Body JJ.
et al.
Management of aromatase inhibitor-associated bone loss in postmenopausal women with breast cancer: Practical guidance for prevention and treatment. Ann Oncol 2011; 22: 2546-2555.
30
Mariz K,
Ingolf J-B,
Daniel H.
et al.
The Wnt inhibitor dickkopf-1: a link between breast cancer and bone metastases. Clin Exp Metastasis 2015; 32 (08) 857-866.
33
Göbel A,
Browne AJ,
Thiele S.
et al.
Potentiated suppression of Dickkopf-1 in breast cancer by combined administration of the mevalonate pathway inhibitors zoledronic acid and statins. Breast Cancer Res Treat 2015; 154: 623-631.
34
Tian E,
Zhan F,
Walker R.
et al.
The Role of the Wnt-Signalling Antagonist DKK1 in the Development of Osteolytic Lesions in Multiple Myeloma. N Engl J Med 2003; 349: 2438-2494.
35
Qiang YW,
Chen Y,
Stephens O.
et al.
Myeloma-derived dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: A potential mechanism underlying osteolytic bone lesions in multiple myeloma. Blood 2008; 112: 196-207.
36
Voorzanger-Rousselot N,
Goehrig D,
Journe F.
et al.
Increased Dickkopf-1 expression in breast cancer bone metastases. Br J Cancer 2007; 97: 964-970.
38
Bu G,
Lu W,
Liu CC.
et al.
Breast cancer-derived Dickkopf1 inhibits osteoblast differentiation and osteoprotegerin expression: Implication for breast cancer osteolytic bone metastases. Int J Cancer 2008; 123: 1034-1042.
39
Mendoza-Villanueva D,
Zeef L,
Shore P.
Metastatic breast cancer cells inhibit osteoblast differentiation through the Runx2/CBFβ-dependent expression of the Wnt antagonist, sclerostin. Breast Cancer Res BioMed Central Ltd 2011; 13: R106.
40
Thudi NK,
Martin CK,
Murahari S.
et al.
Dick- kopf-1 (DKK-1) stimulated prostate cancer growth and metastasis and inhibited bone formation in osteoblastic bone metastases. Prostate 2011; 71: 615-625.
41
Rachner TD,
Thiele S,
Göbel A.
et al.
High serum levels of Dickkopf-1 are associated with a poor prognosis in prostate cancer patients. BMC Cancer 2014; 14: 649.
42
Clézardin P.
Mechanisms of action of bisphosphonates in oncology: a scientific concept evolving from antiresorptive to anticancer activities. Bonekey Rep 2013; 02: 267.
43
Iyer SP,
Beck JT,
Stewart AK.
et al.
A Phase IB multicentre dose-determination study of BHQ880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events. Br J Haematol 2014; 167: 366-375.
44
García-Martín A,
Rozas-Moreno P,
Reyes-García R.
et al.
Circulating levels of sclerostin are increased in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2012; 97: 234-241.
45
Hamann C,
Rauner M,
Höhna Y.
et al.
Sclerostin antibody treatment improves bone mass, bone strength, and bone defect regeneration in rats with type 2 diabetes mellitus. J Bone Miner Res 2013; 28: 627-638.
46
Tsourdi E,
Rijntjes E,
Köhrle J.
et al.
Hyperthyroidism and Hypothyroidism in Male Mice and Their Effects on Bone Mass, Bone Turnover, and the Wnt Inhibitors Sclerostin and Dickkopf-1. Endocrinology 2015; 156: 3517-3527.
