Adipokine adiponectin (APN) has been recently reported to play a role in regulating bone mineral density (BMD). To explore the mechanism by which APN affects BMD, we investigated BMD and biomechanical strength properties of the femur and vertebra in sham-operated (Sham) and ovariectomized (OVX) APN knockout (KO) mice as compared to their operated wild-type (WT) littermates. The results show that APN deficiency has no effect on BMD but induces increased ALP activity and osteoclast cell number. While OVX indeed leads to significant bone loss in both femora and vertebras of WT mice with comparable osteogenic activity and a significant increase in osteoclast cell number when compared to that of sham control. However, no differences in BMD, ALP activity and osteoclast cell number were found between Sham and OVX mice deficient for APN. Further studies using bone marrow derived mesenchymal stem cells (MSCs) demonstrate an enhanced osteogenic differentiation and extracellular matrix calcification in APN KO mice. The possible mechanism for APN deletion induced acceleration of osteogenesis could involve increased proliferation of MSCs and higher expression of Runx2 and Osterix genes. These findings indicate that APN deficiency can protect against OVX-induced osteoporosis in mice, suggesting a potential role of APN in regulating the balance of bone formation and bone resorption, especially in the development of post-menopausal osteoporosis.
References
[1]
Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, et al. (1996) cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun 221: 286–289.
[2]
Berner HS, Lyngstadaas SP, Spahr A, Monjo M, Thommesen L, et al. (2004) Adiponectin and its receptors are expressed in bone-forming cells. Bone 35: 842–849.
[3]
Luo XH, Guo LJ, Yuan LQ, Xie H, Zhou HD, et al. (2005) Adiponectin stimulates human osteoblasts proliferation and differentiation via the MAPK signaling pathway. Exp Cell Res 309: 99–109.
[4]
Luo XH, Guo LJ, Xie H, Yuan LQ, Wu XP, et al. (2006) Adiponectin stimulates RANKL and inhibits OPG expression in human osteoblasts through the MAPK signaling pathway. J Bone Miner Res 21: 1648–1656.
[5]
Shinoda Y, Yamaguchi M, Ogata N, Akune T, Kubota N, et al. (2006) Regulation of bone formation by adiponectin through autocrine/paracrine and endocrine pathways. J Cell Biochem 99: 196–208.
[6]
Oshima K, Nampei A, Matsuda M, Iwaki M, Fukuhara A, et al. (2005) Adiponectin increases bone mass by suppressing osteoclast and activating osteoblast. Biochem Biophys Res Commun 331: 520–526.
[7]
Jürim？e J, Jürim？e T (2007) Plasma adiponectin concentration in healthy preand postmenopausal women: relationship with body composition, bone mineral, and metabolic variables. Am J Physiol Endocrinol Metab 293: E42–E47.
[8]
Richards JB, Valdes AM, Burling K, Perks UC, Spector TD (2007) Serum adiponectin and bone mineral density in women. J Clin Endocrinol Metab 92: 1517–1523.
[9]
Ealey KN, Kaludjerovic J, Archer MC, Ward WE (2008) Adiponectin is a negative regulator of bone mineral and bone strength in growing mice. Exp Biol Med (Maywood) 233: 1546–1553.
[10]
Williams GA, Wang Y, Callon KE, Watson M, Lin JM, et al. (2009) In vitro and in vivo effects of adiponectin on bone. Endocrinology 150: 3603–3610.
[11]
Magni P, Dozio E, Galliera E, Ruscica M, Corsi MM (2010) Molecular Aspects of Adipokine-Bone Interactions. Current Molecular Medicine 10: 522–532.
[12]
Ruscica M, Steffani L, Magni P (2012) Adiponectin interactions in bone and cartilage biology and disease. Vitamins and Hormones 90: 321–339.
[13]
Bacchetta J, Boutroy S, Guebre-Egziabher F, Juillard L, Drai J, et al. (2009) The relationship between adipokines, osteocalcin and bone quality in chronic kidney disease. Nephrol Dial Transplant 24: 3120–3125.
[14]
Ren WH, LI XH, Wang F (2006) Generation of Adiponectin Gene Knock-out and LacZ Gene Knock-in Mouse Model. Prog Bbiochem Biophys 33: 846–853.
[15]
Shu RZ, Zhang F, Wang F, Feng DC, Li XH, et al. (2009) Adiponectin deficiency impairs liver regeneration through attenuating STAT3 phosphorylation in mice. Laboratory Investigation 89: 1043–1052.
[16]
Hankenson KD, Bain SD, Kyriakides TR, Smith EA, Goldstein SA, et al. (2000) Increased marrow-derived osteoprogenitorcells and endosteal bone formation in mice lacking thrombospondin 2. J Bone Miner Res 15: 851–862.
[17]
Yoshimura H, Muneta T, Nimura A, Yokoyama A, Koga H, et al. (2007) Comparison of rat mesenchymal stem cells derived from bone marrow, synovium, periosteum, adipose tissue, and muscle. Cell Tissue Res 327: 449–462.
[18]
Caplan AI, Bruder SP (2001) Mesenchymal stem cells: building blocks for molecular medicine in the 21st century. Trends Mol Med 7: 259–264.
[19]
Caplan AI (1991) Mesenchymal stem cells. J Orthop Res 9: 641–650.
[20]
Khan SN, Cammisa FP Jr, Sandhu HS, Diwan AD, Girardi FP, et al. (2005) The biology of bone grafting. J Am Acad Orthop Surg 13: 77–86.
[21]
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, et al. (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284: 143–147.
[22]
Jaiswal N, Haynesworth SE, Caplan AI, Bruder SP (1997) Osteogenic differentiation of purified, culture-expanded human mesenchymal stem cells in vitro. J Cell Biochem 64: 295–312.
[23]
Zhang H, Xie H, Zhao Q, Xie GQ, Wu XP, et al. (2010) Relationships between serum adiponectin, apelin, leptin, resistin, visfatin levels and bone mineral density, and bone biochemical markers in post-menopausal Chinese women. J Endocrinol Invest 33: 707–711.
[24]
Lei X, Peng X, Wu N, Hu M, Sun Z (2009) Serum adiponectin, leptin level, and bone mineral density in postmenopausal women. Zhong Nan Da Xue Xue Bao Yi Xue Ban 34: 559–562.
[25]
Jürim？e J, Rembel K, Jürim？e T, Rehand M (2005) Adiponectin is associated with bone mineral density in perimenopausal women. Horm Metab Res 37: 297–302.
[26]
Lenchik L, Register TC, Hsu FC, Lohman K, Nicklas BJ, et al. (2003) Adiponectin as a novel determinant of bone mineral density and visceral fat. Bone 33: 646–651.
[27]
Jürim？e J, Jürim？e T (2007) Adiponectin is a predictor of bone mineral density in middle-aged premenopausal women. Osteoporos Int 18: 1253–1259.
[28]
Frost M, Abrahamsen B, Nielsen TL, Frystyk J, Flyvbjerg A, et al. (2007) Adiponectin and peak bone mass in men: a cross-sectional, population-based study. Calcif Tissue Int 87: 36–43.
[29]
Taaffe DR, Cauley JA, Danielson M, Nevitt MC, Lang TF, et al. (2001) Race and sex effects on the association between muscle strength, soft tissue, and bone mineral density in healthy elders: the Health, Aging, and Body Composition Study. J Bone Miner Res 16: 1343–1352.
[30]
Douchi T, Yamamoto S, Kuwahata R, Oki T, Yamasaki H, et al. (2000) Effect of non-weight-bearing body fat on bone mineral density before and after menopause. Obstet Gynecol 96: 13–17.
[31]
Crepaldi G, Romanato G, Tonin P, Maggi S (2007) Osteoporosis and body composition. J Endocrinol Invest 30: 42–47.
[32]
Ijuin M, Douchi T, Matsuo T, Yamamoto S, Uto H, et al. (2002) Difference in the effects of body composition on bone mineral density between pre- and postmenopausal women. Maturitas 43: 239–244.
[33]
Radak TL (2004) Caloric restriction and calcium’s effect on bone metabolism and body composition in overweight and obese premenopausal women. Nutr Rev 62: 468–481.
[34]
Chao D, Espeland MA, Farmer D, Register TC, Lenchik L, et al. (2000) Effect of voluntary weight loss on bone mineral density in older overweight women. J Am Geriatr Soc 48: 753–759.
[35]
Park HA, Lee JS, Kuller LH, Cauley JA (2007) Effects of weight control during the menopausal transition on bone mineral density. J Clin Endocrinol Metab 92: 3809–3815.
[36]
Riedt CS, Cifuentes M, Stahl T, Chowdhury HA, Schlussel Y, et al. (2005) Overweight postmenopausal women lose bone with moderate weight reduction and 1 g/day calcium intake. J Bone Miner Res 20: 455–463.
[37]
Jun AY, Kim HJ, Park KK, Son KH, Lee DH, et al. (2012) Extract of Magnoliae Flos inhibits ovariectomy-induced osteoporosis by blocking osteoclastogenesis and reducing osteoclast-mediated bone resorption. Fitoterapia 83: 1523–1531.
[38]
Rendina E, Lim YF, Marlow D, Wang Y, Clarke SL, et al. (2012) Dietary supplementation with dried plum prevents ovariectomy-induced bone loss while modulating the immune response in C57BL/6J mice. J Nutr Biochm 23: 60–68.
[39]
Luo XH, Zhao LL, Yuan LQ, Wang M, Xie H, et al. (2009) Development of arterial calcification in adiponectin-deficient mice: adiponectin regulates arterial calcification. J Bone Miner Res 24: 1461–1468.
[40]
Buckwalter JA, Cooper RR (1987) Bone structure and function. Instr Course Lect 36: 27–48.
[41]
T Katagiri, N Takahashi (2002) Regulatory mechanisms of osteoblast and osteoclast differentiation. Oral Dis 8: 147–159.
[42]
Karsenty G (2008) Transcriptional Control of Skeletogenesis. Annu Rev Genomics Hum Genet 9: 183–196.
[43]
Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, et al. (2002) The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108: 17–29.
[44]
Tu Q, Zhang J, Dong LQ, Saunders E, Luo E, et al. (2011) Adiponectin inhibits osteoclastogenesis and bone resorption via APPL1-mediated suppression of Akt1. J Biol Chem 286: 12542–12553.
[45]
Yamaguchi N, Kukita T, Li YJ, Martinez Argueta JG, Saito T, et al. (2007) Adiponectin inhibits osteoclast formation stimulated by lipopolysaccharide from Actinobacillus actinomycetemcomitans. FEMS Immunol Med Microbiol 49: 28–34.
[46]
Yamaguchi N, Kukita T, Li YJ, Kamio N, Fukumoto S, et al. (2008) Adiponectin inhibits induction of TNF-alpha/RANKL-stimulated NFATc1 via the AMPK signaling. FEBS Lett 582: 451–456.
