본문 바로가기
HOME> 논문 > 논문 검색상세

논문 상세정보

Effects of Leptin on Osteoclast Generation and Activity

Ko, Seon-Yle    (Dept. of Oral Biochemistry, Dankook University   ); Cho, Sang-Rae    (Dept. of Oral Biochemistry, Dankook University   ); Kim, Se-Won    (Dept. of Dental Pharmacology, Dankook University   ); Kim, Jung-Keun    (Dept. of Oral Biochemistry, Dankook University  );
  • 초록

    Leptin, the product of the obese gene, is a circulating hormone secreted primarily from adipocytes. Several results suggest that leptin is important mediators of bone metabolism. The present study was undertaken to determine the effects of leptin on anti-osteoclastogenesis using murine precursors cultured on Ca-P coated plates and on the production of osteoprotegerin (OPG) in osteoblastic cells. Additionally, this study examined the possible involvement of prostaglandin $E_2\;(PGE_2)$ /protein kinase C (PKC)-mediated signals on the effect of leptin on anti-osteoclastogenesis to various culture systems of osteoclast precursors. Osteoclast generation was determined by counting tartrate-resistant acid phosphatase positive [TRAP (+)] multinucleated cells (MNCs). Osteoclastic activity was determined by measuring area of resorption pits formed by osteoclasts on Ca-P coated plate. The number of 1,25-dihydroxycholecalciferol $(1,25[OH]_2D_3)$ - or $PGE_2$ -induced TRAP (+) MNCs in the mouse bone marrow cell culture decreased significantly after treatment with leptin. The number of receptor activator of NF-kB ligand (RANKL)-induced TRAP (+) MNCs in M-CSF dependent bone marrow macrophage (MDBM) cell or RAW264.7 cell culture decreased significantly with leptin treatment. Indomethacin inhibited osteoclast generation induced by $1,25[OH]_2D_3$ and dexamethasone, however, no significant differences were found in the leptin treated group when compared to the corresponding indomethacin group. Phorbol 12-myristate 13-acetate (PMA), a PKC activator, inhibited osteoclast generation induced by $1,25[OH]_2D_3$ . The number of TRAP (+) MNCs decreased significantly with treatment by PMA at concentrations of 0.01 and $0.1{\mu}M$ in culture. Leptin inhibited PMA-mediated osteoclast generation. Isoquinoline-5-sulfonic 2-methyl-1-piperazide dihydrochloride (H7) had no effect on osteoclast generation induced by $1,25[OH]_2D_3$ . Cell culture treatment with leptin resulted in no significant differences in osteoclast generation compared to the corresponding H7 group. Indomethacin showed no significant effect on TRAP (+) MNCs formation from the RAW264.7 cell line. PMA inhibited TRAP (+) MNCs formation induced by RANKL in the RAW264.7 cell culture. H7 had no effect on osteoclast generation from the RAW264.7 cell line. There was no difference compared with the corresponding control group after treatment with leptin. $1,25[OH]_2D_3$ - or $PGE_2$ -induced osteoclastic activity decreased significantly with leptin treatment at a concentration of 100 ng/ml in mouse bone marrow cell culture. Indomethacin, PMA, and H7 significantly inhibited osteoclastic activity induced by $1,25[OH]_2D_3$ in mouse bone marrow cell culture. No significant differences were found between the leptin treated group and the corresponding control group. The secretion of OPG, a substance known to inhibit osteoclast formation, was detected from the osteoblasts. Treatment by leptin resulted in significant increases in OPG secretion by osteoblastic cells. Taken these results, leptin may be an important regulatory cytokines within the bone marrow microenvironment.


  • 주제어

    Leptin .   Osteoclast.  

  • 참고문헌 (65)

    1. Albala, C., Yanez, M., Devoto, E., Sostin, C., Zeballos, L. and Santos, J.L.: Obesity as a protective factor for postmenopausal osteoporosis. Int. J.Obes. Relat. Metab. Cisord. 20:1027-1032, 1996 
    2. Andersori, D.M., Maraskovsky, E., Billingsley, W.L., Dougall, W.C., Tometsko, M.E., Roux, E.R., Teepe, M.C., DuBose, R.F., Cosman, D. and Galibert, L.: A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390:175-179, 1997 
    3. Collins, S., Kuhn, C.M., Petro, A.E., Swick, A.G., Chrunyk, B.A. and Surwit, R.S.: Role of leptin in fat regulation. Nature 380:677. 1996 
    4. Considine, R.V., Sinha, M.K., Heiman, M.L., Kriauciunas, A., Stephens, T.W., Nyce, M.R., Ohannesian, J.P., Macrco, C.C., McKee, L.J., Bauer, T.L. and Caro, J.F.: Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N. Engl. J. Med. 334:292-295, 1996 
    5. Felson, D.T., Zhang, Y., Hannan, M.T. and Anderson, J.J.: Effects of weight and body mass index on bone mineral density in men and women: The Framinhgam study. J. Bone Miner. Res. 8:567-573, 1993 
    6. Lengauer, C., Kinzler, K.W. and Vogelstein, B.: Genetic instabilities in human cancers. Nature 396:643-649, 1998 
    7. Liu, B.Y., Guo, J., Lanske, B., Divieti, P., Kronenberg, H.M. and Bringhurst, F.R.: Conditionally immortalized murine bone marrow stromal cells mediate parathyroid hormonedependent osteoclastogenesis in vitro. Endocrinology 139: 1952-1964, 1998 
    8. Matkovic, V., Ilich, J.Z., Badenhop, N.E., Skugor, M., Clairmont, A., Klisovic, D. and Landoll, J.D.: Gain in body fat is inversely related to the nocturnal rise in serum leptin level in young females. J. Clin. Endocrinol. Metab. 82: 1368-1372, 1997 
    9. Pasco, J.A., Henry, M.J., Kotowicz, M.A., Collier, G.R., Ball, M.J., Ugoni, A.M. and Nicholson, G.C.: Serum leptin levels are associated with bone mass in nonobese women. J. Clin. Endocrinol. Metab. 86:1884-1887, 2001 
    10. Roodman, G.D.: Cell biology of the osteoclast. Exp. Hematol. 27: 1299-1241, 1999 
    11. Suda, T., Takahashi, N. and Martin, T.J.: Modulation of osteoclast differentiation. Endocrine Rev. 13:66-80, 1992 
    12. Takahashi, N., Udagawa, N. and Suda, T.: A new member of tumor necrosis factor ligand family, RANKL/OPGL/TRANCE/RANKL, regulates osteoclast differentiation and function. Biochem. Biophys. Res. Commun. 256:449-455, 1999 
    13. Takekoshi, K., Ishii, K., Nanmoku, T., Shibuya, S., Kawakami, Y., Isobe, K. and Nakai T.: Leptin stimulates catecholamine synthesis in a PKC-dependent manner in cultured porcine adrenal medullary chromaffin cells. Endocrinology 142:4861-4871, 2001 
    14. Yamauchi, M., Sugimoto, T., Yamaguchi, T., Nakaoka, D., Kanzawa, M., Yano, S., Ozuru, R., Sugishita, T. and Chihara, K.: Plasma leptin concentrations are associated with bone mineral density and the presence of vertebral fractures in postmenopausal women. Clin. Endocrinol. 55:341-347, 2001 
    15. Burgess, T.L., Qian, Y., Kaufman, S., Ring, B.D., Van, G., Capparelli, C., Kelley, M., Hsu, H., Boyle, W.J., Dunstan, C.R., Hu, S. and Lacey, D.L.: The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. J. Cell Biol. 145:527-538, 1999 
    16. Fleet, J.C.: Leptin and bone: does the brain control bone biology? Nutrition Rev. 58:209-211, 2000 
    17. Moonga, B.S. and Dempster, D.W.: Effects of peptide fragments of protein kinase C on isolated rat osteoclasts. Exp. Physiol. 83:717-725, 1998 
    18. Cornish, J., Callon, K.E., Bava, U., Lin, C., Naot, D., Hill, B.L., Grey, A.B., Broom, N., Myers, D.E., Nicholson, G.C. and Reid, I.R.: Leptin directly regulates bone cell function in vitro and reduces bone fragility in vivo. J. Endocrinol. 175:405-415, 2002 
    19. Minkin, C.: Bone acid phosphatase: Tartrate-resistant acid phosphatase as a marker of osteoclast function. Calcif. Tissue Int. 34:285-290, 1982 
    20. Bado, A., Levasseur, S., Attoub, S., Kermorgant, S., Laigneau, J.P. Bortoluzzi, M.N., Moizo, L., Lehy, T., Guerre-Millo, M., LeMarchand-Brustel, Y. and Lewin, M.J.: The stomach is a source of leptin. Nature 394:790-793, 1998 
    21. Ducy, P., Amling, M., Takeda, S., Priemel, M., Schilling, A.F., Beil, F.T., Shen, J., Vinson, C., Rueger, J.M. and Karsenty, G.: Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100:197-207, 2000 
    22. Steppan, C.M. and Swick, A.G.: A role for leptin in brain development. Biophy. Biochem. Res. Commun. 256:600-602, 1999 
    23. Hoover, P.A., Webber, C.E., Beaumont, .L.F. and Blake, J.M.: Postmenopausal bone mineral density: relationship to calcium intake, calcium absorption, residual estrogen, body composition, and physical activity. Can. J. Physiol. Pharmacol. 74:911-917, 1996 
    24. Solin, M.S., Ball, M.J., Robertson, I. De Silva, A., Pasco, J., Kotowicz, M.A., Nicholson, G.C. and Collier, G.R.: Relationship of serum leptin to total and truncal body fat. Clin. Sci. 93:581-584, 1997 
    25. Chambers, T.: Regulation of osteoclast development and function. In Rifkin B., Gay, C. edited. Biology and Physiology of the osteoclast. CRC Press, Boca Raton, FL, USA pp 105-128, 1992 
    26. Frost, H.M.: Metabolism of bone. N. Engl. J. Med. 289:864-865, 1973 
    27. Gordeladze, J.O., Drevon, C.A., Syversen, U. and Reseland, J.E.: Leptin stimulates human osteoblastic cell proliferation, de novo collagen synthesis, and mineralization: Impact on differentiation markers, apoptosis, and osteoclastic signaling. J. Cell. Biochem. 85:825-836, 2002 
    28. Reid, I.R., Ames, R., Evans, M.C., Sharpe, S., Gamble, G., France, J.T., Lim, T.M. and Cundy, T.F.: Determinants of total body and regional bone' mineral density in normal postmenopausal women-a key role for fat mass. J. Clin. Endocrinol. Metob. 75:45-51, 1992 
    29. Huang, L. and Cai, L.: Leptin: a multifunctional hormone. Cell Research 10: 81-92, 2000 
    30. Mundy, G.R. and Roodman, G.D.: Osteoclast ontogeny and function, In Bone and Mineral Research, vol. 5, edited by Peck, W.A., pp 209-279, Elsevier, Amsterdam, 1987 
    31. Ogueh, O., Sooranna, S., Nicolaides, K.H. and Johnson, M.R.: The relationship between leptin concentration and bone metabolism in the human fetus. J. Clin. Endocrinol. Metab. 85:1997-1999, 2000 
    32. Anselme, K., Noel, B., Limosino, D., Bianchi, F., Morin, C. and Hardouin, P.: Comparative study of the in vitro characteristics of osteoblasts from paralytic and nonparalytic children. Spinal Cord 38:622-629, 2000 
    33. Eastel, R.: Pathogenesis of postmenopausal osteoporosis. In Favus, M.J. edited. Primer on the metabolic bone diseases and disorders of mineral metabolism, 4th ed. Philadelpia, PA : Lippincott Wiliams and Wilkins, pp 260-262, 1999 
    34. Iwaniec, U.T., Baumann, G., Heinzmann, U. and Atkinson, M.J.: Loss of the differentiated phenotype precedes apoptosis of ROS 17/2.8 osteoblast-like cells. Calcif. Tissue Int. 63: 208-213, 1998 
    35. Kodama, H., Yamasaki, A., Nose, M., Niida, S., Ohgame, Y, Abe, M., Kumegawa, M. and Suda, T.: Congenital osteoclast deficiency in osteopetrotic (op/op) mice is cured by injections of macrophage colony-stimulating factor. J. Exp. Med.173:269-272, 1991 
    36. Laharrague, P., Larrouy, D., Fontanilles, A.M., Truel, N., Campfield, A, Tenenbaum, R., Galitzky, J., Corberand, J.X., Penicaud, L. and Casteilla, L.: High expression of leptin by human bone marrow adipocytes in primary culture. FASEB J. 12:747-752, 1998 
    37. Ravn, P., Cizza, G., Bjarnason, N.H., Thompson, D., Daley, M., Wasnich, R.D., McClung, M., Hosking, D., Yates, A.J. and Christiansen, C.: Low Body Mass Index Is an Important Risk Factor for Low Bone Mass and Increased Bone Loss in Early Postmenopausal Women. J. Bone Miner. Res. 14: 1622-1627, 1999 
    38. Suda, T., Takahashi, N., Udagawa, N., limi, E., Gillespie, M.T. and Martin, T.J.: Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocrine Rev. 20:345-57, 1999 
    39. Udagawa, N., Takahashi, N., Yasuda, H., Mizuno, A., Itoh, K., Ueno, Y., Shinki, T., Gillespie, M.T., Martin, T.J., Higashio, K. and Suda, T.: Osteoprotegerin produced by osteoblasts is an important regulator in osteoclast development and function. Endocrinology 141:3478-3484, 2000 
    40. Lord, G.M., Matarese, G., Howard, J.K., Baker, R.J., Bloom, S.R. and Lechler, R.I.: Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394:897-901, 1998 
    41. Kondo, H., Guo, J. and Bringhurst, F.R.: Cyclic adenosine monophosphate/protein kinase A mediates parathyroid hormone/parathyroid hormone-related protein receptor regulation of osteoclastogenesis and expression of RANKL and osteoprotegerin mRNAs by marrow stromal cells. J. Bone Miner. Res. 17:1667-1679, 2002 
    42. Stein, G.S., Lian, J.B., Stein, J.L., Van Wijnen, A.J. and Montecino, M.: Transcriptional control of osteoblast growth and differentiation. Physiol. Rev. 76: 593-629, 1996 
    43. Sierra-Honigmann, M.R., Nath, A.K., Murakami, C., GarciaCardena, G., Papapetropoulos, A., Sessa, W.C., Madge, L.A., Schechner, J.S., Schwabb, M.B., Polverini, P.J. and Flores-Riveros, J.R.: Biological action of leptin as an angiogenic factor. Science 281: 1683-1686, 1998 
    44. Klein, S., Coppack, S.W., Mohamed-Ali, V. and Landt, M.: Adipose tissue leptin production and plasma leptin kinetics in humans. Diabetes 45:984-987, 1996 
    45. Shimabukuro, M., Koyama, K., Chen, G., Wang, M.Y., Trieu, F., Lee, Y., Newgard, C.B. and Unger, R.H.: Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proc. Natl. Aacd. Sci. 94:4637-4641, 1997 
    46. Cohen, B., Novick, D. and Rubinstein, M.: Modulation of insulin activities by leptin. Science 274:1185-1188, 1996 
    47. Considine, R.V. and Caro, J.F.: Pleiotropic cellular effects of leptin. Curr. Opin. Endocrinol. Diabetes 6:163-169, 1999 
    48. Gainsford, T., Willson, T.A., Metcalf, D., Handman, E., McFarlane, C., Ng, A., Nicola, N.A., Alexander, W.S. and Hilton, D.J.: Leptin can induce proliferation, differentiaion, and functional activation of hemopoietic cells. Proc. Natl. Acad. Sci. 93:14564-14568, 1996 
    49. Liu, C., Grossmann, A., Bain, S., Srachan, M., Puemer, D., Bailey, C., Humes, J., Lenox, J., Yamamoto, G., Sprugel, K., Kuijper, J., Weigle, S., Dunam, D. and Moore, E.: Leptin stimulates cortical bone formation in obese (ob/ob) mice. Annual Meeting of the ASBMR (abstract) S211 :50, 1997 
    50. Santos-Alvarez, J., Goberna, R. and Sancez-Margalet, V.: Human leptin stimulates proliferation and activation of human circulating monocytes. Cell Immunol. 194: 6-11, 1999 
    51. Nijweide, P.J., Burger, E.H. and Feyen, J.H.M.: Cells of bone: Proliferation, differentiation, and hormonal regulation. Physiol. Rev. 66:855-886, 1986 
    52. Ribot, C., Tremollieres, F. and Pouilles, J.M.: The effect of obesity on postmenopausal bone loss and the risk of osteoporosis. Adv. Natr. Res. 9:257-271, 1994 
    53. Hsu, H., Lacey, D.L., Dunstan, C.R., Solovyev, I., Colombero, A., Timms, E., Tan, H.L., Elliott, G., Kelley, M.J., Sarosi, I., Wang, L., Xia, X.L., Elliott, R., Chiu, L., Black, T., Scully, S., Capparelli, C., Morony, S., Shimamoto, G., Bass, M.B. and Boyle, W.J.: Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc. Natl. Acad. Sci. USA 96:3540-3545, 1999 
    54. Tartaglia, L.A.: The leptin receptor. J. Biol. Chem. 272.:6093-6096, 1997 
    55. Yasuda, H., Shima, N., Nakagawa, N., Yamaguchi, K., Kinosaki, M., Mochizuki, S., Tomoyasu, A., Yano, K., Goto, M., Murakami, A., Tsuda, E., Morinaga, T., Higashio, K., Udagawa, N., Takahashi, N. and Suda, T.: Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclasto-genesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl. Acad. Sci. USA 95:3597-3602, 1998 
    56. Klein, K.O., Larmore, K.A., de Lancey, E., Brown, J.M., Considine, R.V. and Hassink, S.G: Effect of obesity on estradiol level, and its relationship to leptin, bone maturation, and bone mineral density in children. J. Clin. Endocrinol. Metab. 83:3469-3475, 1998 
    57. Kong, Y.Y., Yoshida, H., Sarosi, I., Tan, H.L., Timms, E., Capparelli, C., Morony, S., Oliveira-dos-Santos, A.J., Van, G., Itie, A., Khoo, W., Wakeham, A., Dunstan, C.R., Lacey, D.L., Mak, T.W., Boyle, W.J. and Penninger, J.M.: OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397: 315-323, 1999b 
    58. Maor, G., Rochwerger, M., Segev, Y. and Phillip, M.: Leptin acts as a growth factor on the chondrocytes of skeletal growth centers. J. Bone Miner. Res. 17:1034-1043, 2002 
    59. Thomas, T., Gori, F., Khosla, S., Jensen, M.D., Burguera, B. and Riggs, B.L.: Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology 140: 1630-1638, 1999 
    60. Barash, I.A., Cheung, C.C., Weigle, D.S., Kabigting, E.B., Kuijper, J.L., Clifton, D.K. and Steiner, R.A.: Leptin is a metabolic signal to the reproductive system. Endocrinology 137:3144-3147, 1996 
    61. Ranganathan, S., Ciaraldi, T.P., Henry, R.R., Mudaliar, S. and Kern, P.A.: Lack of effect of leptin on glucose transport, lipoprotein lipase, and insulin action in adipose and muscle cells. Endocrinology 139:2509-2513, 1998 
    62. Steppan, C.M., Crawford, D.T., Chidsey-Frink, K.L., Ke, H. and Swick, A.G.: Leptin is a potent stimulator of bone growth in ob/ob mice. Regul. Pept. 92:73-78, 2000 
    63. Wong, B.R., Rho, J., Arron, J., Robinson, E., Orlinick, J., Chao, M., Kalachilov, S., Cayani, E., Bartlett, III, F.S., Frankel, W.N., Lee, S.Y. and Choi, Y.: TRANCE is a novel ligand of the tumor necrosis factor receptor family that activated c-Jun N-terminal kinase in T cells. J. Biol. Chem. 272:25190-25194, 1997 
    64. Begg, S.K., Radley, J.M., Pollard, J.W., Chisholm, O.T., Stanley, E.R. and Bertoncello, I.: Delayed hematopoietic development in osteopetrotic (op/op) mice. J. Exp. Med. 177:237-242, 1993 
    65. Holloway, W.R., Collier, F.M., Aitken, C.J., Myers, D.E., Hodge, J.M., Malakellis, M., Gough, T.J., Collier, G.R. and Nicholson, G.C.: Leptin inhibits osteoclast generation. J. Bone Miner. Res. 17:200-209, 2002 

 저자의 다른 논문

  • Ko, Seon-Yle (20)

    1. 2000 "Effect of Atrial Natriuretic Peptide on the Proliferation and Activity of Osteoblastic Cells" The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 4 (4): 283~289    
    2. 2000 "마우스 골수세포 배양시 transforming growth factor-β와 epidermal growth factor가 파골세포양세포의 형성에 미치는 영향" 대한구강내과학회지 = Korean journal of oral medicine 25 (1): 53~62    
    3. 2001 "Endothelin-1이 HOS 세포의 증식과 활성에 미치는 영향" 대한구강내과학회지 = Korean journal of oral medicine 26 (4): 319~329    
    4. 2003 "법랑기질 단백질 유도체가 치주인대양세포 및 조골양세포에 미치는 영향" 대한치주과학회지 = The journal of Korean academy of periodontology 33 (2): 225~246    
    5. 2005 "뼈흡수유도호르몬이 ROS17/2.8세포로부터 Nitric Oxide 형성에 미치는 영향" 대한구강악안면방사선학회지 = Korean journal of oral and maxillofacial radiology 35 (3): 127~131    
    6. 2005 "Effects of Achyranthes Radix Extracts on Osteoblasts and Osteocalsts" International journal of oral biology : official journal of the Korean Academy of Oral Biology and the UCLA Dental Research Institute 30 (2): 39~45    
    7. 2005 "Pyrroloquinoline quinone이 파골세포의 생성 및 활성에 미치는 영향" 대한구강내과학회지 = Korean journal of oral medicine 30 (3): 329~336    
    8. 2006 "Effects of Interleukin-$1\beta$, Tumor Necrosis Factor-$\alpha$ and Interferon-$\gamma$ on the Nitric Oxide Production and Osteoclast Generation in the Culture of Mouse Bone Marrow Cells" International journal of oral biology : official journal of the Korean Academy of Oral Biology and the UCLA Dental Research Institute 31 (2): 67~72    
    9. 2006 "Angiopoietin-2가 조골세포와 파골세포의 성장과 활성에 미치는 영향" 대한구강내과학회지 = Korean journal of oral medicine 31 (1): 17~25    
    10. 2006 "The Effects of Hesperidin on the Proliferation and Activity of Bone Cells" International journal of oral biology : official journal of the Korean Academy of Oral Biology and the UCLA Dental Research Institute 31 (4): 119~125    
  • Kim, Jung-Keun (23)

 활용도 분석

  • 상세보기

    amChart 영역
  • 원문보기

    amChart 영역

원문보기

무료다운로드
유료다운로드

유료 다운로드의 경우 해당 사이트의 정책에 따라 신규 회원가입, 로그인, 유료 구매 등이 필요할 수 있습니다. 해당 사이트에서 발생하는 귀하의 모든 정보활동은 NDSL의 서비스 정책과 무관합니다.

원문복사신청을 하시면, 일부 해외 인쇄학술지의 경우 외국학술지지원센터(FRIC)에서
무료 원문복사 서비스를 제공합니다.

NDSL에서는 해당 원문을 복사서비스하고 있습니다. 위의 원문복사신청 또는 장바구니 담기를 통하여 원문복사서비스 이용이 가능합니다.

이 논문과 함께 출판된 논문 + 더보기