Adipokine und Knochenstoffwechsel – gibt es einen Link?

Zusammenfassung

Während sich Ab- und Aufbauprozesse des Knochens im Körper eines gesunden Erwachsenen die Waage halten, können Störungen des Knochenstoffwechsels dazu führen, dass ein Ungleichgewicht entsteht, welches in einer pathologischen Veränderung der Knochendichte, wie bei der Osteoporose, oder der pathologischen Neubildung von Knochenstrukturen, wie bei der ankylosierenden Spondylitis, resultiert. Aktivität und Differenzierung der knochenbildenden Zellen, der Osteoblasten, und der knochenabbauenden Zellen, der Osteoklasten, sind die wesentlichen Faktoren, welche Knochenauf- und -abbau bestimmen. Zahlreiche Moleküle sind an der Regulierung dieser Vorgänge beteiligt, darunter RANKL, OPG und verschiedene inflammatorische Faktoren. Letztere wurden in jüngerer Zeit durch die sogenannten Adipokine, einer Gruppe zytokinähnlicher Proteine, welche zuerst in Fettgewebe identifiziert wurden, die jedoch auch von weiteren Zelltypen produziert werden, erweitert. Diese Übersichtsarbeit geht der Frage nach, ob und ggf. wie Adipokine Einfluss auf den Knochenstoffwechsel nehmen können und ob eine Korrelation zur Knochendichte besteht. Dazu wird ein Überblick über die Forschungsergebnisse aus in vitro-Analysen, Tierexperimenten und klinischen Studien gegeben. Diese zeigen deutlich auf, dass ein Link zwischen Adipokinen und dem Knochenstoffwechsel bzw. den Zellen des Knochenstoffwechsels besteht. Die tatsächliche Wirkung der Adipokine auf den Knochen im menschlichen Organismus scheint jedoch von einer Vielzahl weiterer Faktoren abzuhängen, da je nach experimentellem und klinischem Modell deutliche Diskrepanzen zwischen den verschiedenen Ergebnissen bestehen.

Abstract

While there is a homeostasis between bone formation and bone resorption in the healthy organism of human adults, disorders of bone metabolism can disrupt this balance resulting in pathological changes of bone density as in osteoporosis or the pathological formation of new bone structures as in ankylosing spondylitis. The activity and differentiation of bone-forming osteoblasts and bone-resorbing osteoclasts are the key factors determining the actual balance or dysbalance of bone metabolism. A wide spectrum of molecules is involved in regulating these processes including RANKL, OPG and several inflammation-related factors. Recently, the so-called adipokines, a group of cytokine-like mediators first discovered in adipose tissue but also produced by various other cell types, have been added to this spectrum. In this review, we addressed whether and how adipokines affect bone metabolism and whether there is a correlation with bone density. For this, an overview of research results from in vitro analyses, animal experiments and clinical studies is provided. The results clearly show a link between adipokines and bone metabolism. However, the actual effect of adipokines on bone in the human organism appears to be dependent on numerous other factors as there are, in part, obvious discrepancies between these results depending on the respective experimental model or clinical setting.

Schlüsselwörter

Adipokine - Knochenmetabolismus - Osteoblasten - Osteoklasten - Knochendichte

Key words

adipokines - bone metabolism - osteoblasts - osteoclasts - bone density

• Literatur

• 1 Neumann E, Schett G. Bone metabolism: molecular mechanisms. Z Rheumatol 2007; 66: 286-289
• 2 Coppack SW. Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc 2001; 60: 349-356
• 3 Berner HS, Lyngstadaas SP, Spahr A et al. Adiponectin and its receptors are expressed in bone-forming cells. Bone 2004; 35: 842-849
• 4 Ehling A, Schäffler A, Herfarth H et al. The potential of adiponectin in driving arthritis. J Immunol 2006; 176: 4468-4478
• 5 Kanazawa I, Yamaguchi T, Yano S et al. Adiponectin and AMP kinase activator stimulate proliferation, differentiation, and mineralization of osteoblastic MC3T3-E1 cells. BMC Cell Biol 2007; 8: 51
• 6 Shinoda Y, Yamaguchi M, Ogata N et al. Regulation of bone formation by adiponectin through autocrine/paracrine and endocrine pathways. J Cell Biochem 2006; 99: 196-208
• 7 Thommesen L, Stunes AK, Monjo M et al. Expression and regulation of resistin in osteoblasts and osteoclasts indicate a role in bone metabolism. J Cell Biochem 2006; 99: 824-834
• 8 Schäffler A, Ehling A, Neumann E et al. Adipocytokines in synovial fluid. JAMA 2003; 290: 1709-1710
• 9 Klein-Wieringa IR, Kloppenburg M, Bastiaansen-Jenniskens YM et al. The infrapatellar fat pad of patients with osteoarthritis has an inflammatory phenotype. Ann Rheum Dis 2011; 70: 851-857
• 10 Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006; 6: 772-783
• 11 Neumann E, Frommer KW, Vasile M et al. Adipocytokines as driving forces in rheumatoid arthritis and related inflammatory diseases?. Arthritis Rheum 2011; 63: 1159-1169
• 12 Luo X-H, Guo L-J, Xie H et al. Adiponectin stimulates RANKL and inhibits OPG expression in human osteoblasts through the MAPK signaling pathway. J Bone Miner Res 2006; 21: 1648-1656
• 13 Williams GA, Wang Y, Callon KE et al. In vitro and in vivo effects of adiponectin on bone. Endocrinology 2009; 150: 3603-3610
• 14 Lee HW, Kim SY, Kim AY et al. Adiponectin stimulates osteoblast differentiation through induction of COX2 in mesenchymal progenitor cells. Stem Cells 2009; 27: 2254-2262
• 15 Oshima K, Nampei A, Matsuda M et al. Adiponectin increases bone mass by suppressing osteoclast and activating osteoblast. Biochem Biophys Res Commun 2005; 331: 520-526
• 16 Yamaguchi N, Kukita T, Li Y-J et al. Adiponectin inhibits induction of TNF-alpha/RANKL-stimulated NFATc1 via the AMPK signaling. FEBS Lett 2008; 582: 451-456
• 17 Mitsui Y, Gotoh M, Fukushima N et al. Hyperadiponectinemia enhances bone formation in mice. BMC Musculoskelet Disord 2011; 12: 18
• 18 Tu Q, Zhang J, Dong LQ et al. Adiponectin inhibits osteoclastogenesis and bone resorption via APPL1-mediated suppression of Akt1. J Biol Chem 2011; 286: 12542-12553
• 19 Cirmanova V, Bayer M, Starka L et al. The effect of leptin on bone: an evolving concept of action. Physiol Res 2008; 57 (Suppl. 01) S143-S151
• 20 Ducy P, Amling M, Takeda S et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 2000; 100: 197-207
• 21 Bertoni L, Ferretti M, Cavani F et al. Leptin increases growth of primary ossification centers in fetal mice. J Anat 2009; 215: 577-583
• 22 Turner RT, Kalra SP, Wong CP et al. Peripheral leptin regulates bone formation. J Bone Miner Res 2013; 28: 22-34
• 23 Bartell SM, Rayalam S, Ambati S et al. Central (ICV) leptin injection increases bone formation, bone mineral density, muscle mass, serum IGF-1, and the expression of osteogenic genes in leptin-deficient ob/ob mice. J Bone Miner Res 2011; 26: 1710-1720
• 24 Patel L, Buckels AC, Kinghorn IJ et al. Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. Biochem Biophys Res Commun 2003; 300: 472-476
• 25 Bokarewa M, Nagaev I, Dahlberg L et al. Resistin, an adipokine with potent proinflammatory properties. J Immunol 2005; 174: 5789-5795
• 26 Xie H, Tang S-Y, Luo X-H et al. Insulin-like effects of visfatin on human osteoblasts. Calcif Tissue Int 2007; 80: 201-210
• 27 Li Y, He X, He J et al. Nicotinamide phosphoribosyltransferase (Nampt) affects the lineage fate determination of mesenchymal stem cells: a possible cause for reduced osteogenesis and increased adipogenesis in older individuals. J Bone Miner Res 2013; 26: 2656-2664
• 28 Moschen AR, Geiger S, Gerner R et al. Pre-B cell colony enhancing factor/NAMPT/visfatin and its role in inflammation-related bone disease. Mutat Res 2010; 690: 95-101
• 29 Venkateshaiah SU, Khan S, Ling W et al. NAMPT/PBEF1 enzymatic activity is indispensable for myeloma cell growth and osteoclast activity. Exp Hematol 2013; 41 (547–557) e542
• 30 Zhu X, Jiang Y, Shan PF et al. Vaspin attenuates the apoptosis of human osteoblasts through ERK signaling pathway. Amino Acids 2013; 44: 961-968
• 31 Kamio N, Kawato T, Tanabe N et al. Vaspin attenuates RANKL-induced osteoclast formation in RAW264.7 cells. Connect Tissue Res 2013; 54: 147-152
• 32 Muruganandan S, Roman AA, Sinal CJ. Role of chemerin/CMKLR1 signaling in adipogenesis and osteoblastogenesis of bone marrow stem cells. J Bone Miner Res 2010; 25: 222-234
• 33 Muruganandan S, Dranse HJ, Rourke JL et al. Chemerin neutralization blocks hematopoietic stem cell osteoclastogenesis. Stem Cells 2013; 31: 2172-2182
• 34 Xie H, Xie PL, Luo XH et al. Omentin-1 exerts bone-sparing effect in ovariectomized mice. Osteoporos Int 2012; 23: 1425-1436
• 35 Wu SS, Liang QH, Liu Y et al. Omentin-1 Stimulates Human Osteoblast Proliferation through PI3K/Akt Signal Pathway. Int J Endocrinol 2013; 2013: 368970.
• 36 Assadi M, Salimipour H, Akbarzadeh S et al. Correlation of circulating omentin-1 with bone mineral density in multiple sclerosis: the crosstalk between bone and adipose tissue. PLoS One 2011; 6: e24240
• 37 Barbour KE, Zmuda JM, Boudreau R et al. Adipokines and the risk of fracture in older adults. J Bone Miner Res 2011; 26: 1568-1576
• 38 Michaelsson K, Lind L, Frystyk J et al. Serum adiponectin in elderly men does not correlate with fracture risk. J Clin Endocrinol Metab 2008; 93: 4041-4047
• 39 Biver E, Salliot C, Combescure C et al. Influence of adipokines and ghrelin on bone mineral density and fracture risk: a systematic review and meta-analysis. J Clin Endocrinol Metab 2011; 96: 2703-2713
• 40 Wolf G. Energy regulation by the skeleton. Nutr Rev 2008; 66: 229-233
• 41 Schwetz V, Pieber T, Obermayer-Pietsch B. The endocrine role of the skeleton: background and clinical evidence. Eur J Endocrinol 2012; 166: 959-967
• 42 Gravenstein KS, Napora JK, Short RG et al. Cross-sectional evidence of a signaling pathway from bone homeostasis to glucose metabolism. J Clin Endocrinol Metab 2011; 96: E884-E890
• 43 Buday B, Pach FP, Literati-Nagy B et al. Serum osteocalcin is associated with improved metabolic state via adiponectin in females versus testosterone in males. Gender specific nature of the bone-energy homeostasis axis. Bone 2013; 57: 98-104
• 44 Lenchik L, Register TC, Hsu FC et al. Adiponectin as a novel determinant of bone mineral density and visceral fat. Bone 2003; 33: 646-651
• 45 Iacobellis G, Iorio M, Napoli N et al. Relation of adiponectin, visfatin and bone mineral density in patients with metabolic syndrome. J Endocrinol Invest 2010; 34: e12-e15
• 46 Gonnelli S, Caffarelli C, Del Santo K et al. The relationship of ghrelin and adiponectin with bone mineral density and bone turnover markers in elderly men. Calcif Tissue Int 2008; 83: 55-60
• 47 Oh KW, Lee WY, Rhee EJ et al. The relationship between serum resistin, leptin, adiponectin, ghrelin levels and bone mineral density in middle-aged men. Clin Endocrinol (Oxf) 2005; 63: 131-138
• 48 Tohidi M, Akbarzadeh S, Larijani B et al. Omentin-1, visfatin and adiponectin levels in relation to bone mineral density in Iranian postmenopausal women. Bone 2012; 51: 876-881
• 49 Wang D, Jiang TJ, Liao L et al. Relationships between serum omentin-1 concentration and bone mineral density, and bone biochemical markers in Chinese women. Clin Chim Acta 2013; 426: 64-67
• 50 Guo LJ, Jiang TJ, Liao L et al. Relationship between serum omentin-1 level and bone mineral density in girls with anorexia nervosa. J Endocrinol Invest 2013; 36: 190-194