Periodontal ligament (PDL) cells play an essential role in orthodontic tooth movement. We recently reported that clodronate, a non-N-containing bisphosphonate, strongly inhibited tooth movement in rats, and thus could be a useful adjunct for orthodontic treatment. However, it is not clear how clodronate affects the responses of PDL cells to orthodontic force. In this study, we hypothesized that clodronate prevents the mechanical stress-induced production of prostaglandin E2 (PGE2), interleukin-1β (IL-1β), and nitric oxide (NO) in human PDL cells. A compressive stimulus caused a striking increase in PGE2 production, while the responses of IL-1β and NO were less marked. Clodronate concentration-dependently inhibited the stress-induced production of PGE2. Clodronate also strongly inhibited stress-induced gene expression for COX-2 and RANKL. These results suggest that the inhibitory effects of clodronate on tooth movement and osteoclasts may be due, at least in part, to the inhibition of COX-2-dependent PGE2 production and RANKL expression in PDL cells.
Get full access to this article
View all access options for this article.
References
1.
Alhashimi N, Frithiof L, Brudvik P, Bakhiet M -2001-. Orthodontic tooth movement and de novo synthesis of proinflammatory cytokines. Am J Orthod Dentofacial Orthop119:307–312.
2.
Buttery LDK, Mancini L, Moradi-Bidhendi N, O’Shaughnessy MC, Polak JM, MacIntyre I -2002-. Nitric oxide and other vasoactive agents. In: Principles of bone biology. 2nd ed. Vol. 2. Bilezikian JP, Raisz LG, Rodan GA, editors. San Diego: Academic Press, pp. 995–1013.
3.
Chumbley AB, Tuncay OC -1986-. The effect of indomethacin -an aspirin-like drug- on the rate of orthodontic tooth movement. Am J Orthod89:312–314.
4.
Felix R, Bettex JD, Fleisch H -1981-. Effect of diphosphonates on the synthesis of prostaglandins in cultured calvaria cells. Calcif Tissue Int33:549–552.
5.
Fleisch H -2000-. Bisphosphonates in bone disease: from the laboratory to the patient. 4th ed. San Diego: Academic Press, pp. 40–41.
6.
Frith JC, Mönkkönen J, Auriola S, Mönkkönen H, Rogers MJ -2001-. The molecular mechanism of action of the antiresorptive and antiinflammatory drug clodronate: evidence for the formation in vivo of a metabolite that inhibits bone resorption and causes osteoclast and macrophage apoptosis. Arthritis Rheum44:2201–2210.
7.
Halasy-Nagy JM, Rodan GA, Reszka AA -2001-. Inhibition of bone resorption by alendronate and risedronate does not require osteoclast apoptosis. Bone29:553–559.
8.
Hayashi K, Igarashi K, Miyoshi K, Shinoda H, Mitani H -2002-. Involvement of nitric oxide in orthodontic tooth movement in rats. Am J Orthod Dentofacial Orthop122:306–309.
9.
Igarashi K, Mitani H, Adachi H, Shinoda H -1994-. Anchorage and retentive effects of a bisphosphonate -AHBuBP- on tooth movements in rats. Am J Orthod Dentofacial Orthop106:279–289.
10.
Igarashi K, Hirafuji M, Adachi H, Shinoda H, Mitani H -1997-. Effects of bisphosphonates on alkaline phosphatase activity, mineralization, and prostaglandin E2 synthesis in the clonal osteoblast-like cell line MC3T3-E1. Prostaglandins Leukot Essent Fatty Acids56:121–125.
11.
Iwasaki LR, Haack JE, Nickel JC, Reinhardt RA, Petro TM -2001-. Human interleukin-1 beta and interleukin-1 receptor antagonist secretion and velocity of tooth movement. Arch Oral Biol46:185–189.
12.
Kanzaki H, Chiba M, Shimizu Y, Mitani H -2002-. Periodontal ligament cells under mechanical stress induce osteoclastogenesis by receptor activator of nuclear factor kappaB ligand up-regulation via prostaglandin E2 synthesis. J Bone Miner Res17:210–220.
13.
Lacey DL, Tan HL, Lu J, Kaufman S, Van G, Qiu W, et al. -2000-. Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo. Am J Pathol157:435–448.
14.
Liu L, Igarashi K, Haruyama N, Saeki S, Shinoda H, Mitani H -2004-. Effects of local administration of clodronate on orthodontic tooth movement and root resorption in rats. Eur J Orthod26:469–473.
15.
Makkönen N, Hirvonen MR, Teräväinen T, Savolainen K, Mönkkönen J -1996-. Different effects of three bisphosphonates on nitric oxide production by RAW 264 macrophage-like cells in vitro. J Pharmacol Exp Ther277:1097–1102.
16.
Makkönen N, Salminen A, Rogers MJ, Frith JC, Urtti A, Azhayeva E, et al. -1999-. Contrasting effects of alendronate and clodronate on RAW 264 macrophages: the role of a bisphosphonate metabolite. Eur J Pharm Sci8:109–118.
17.
Ohta K, Araki N, Shibata M, Hamada J, Komatsumoto S, Shimazu K, et al. -1994-. A novel in vivo assay system for consecutive measurement of brain nitric oxide production combined with the microdialysis technique. Neurosci Lett176:165–168.
18.
Österman T, Kippo K, Lauren L, Hannuniemi R, Sellman R -1995-. Effect of clodronate on established collagen-induced arthritis in rats. Inflamm Res44:258–263.
19.
Pennanen N, Lapinjoki S, Urtti A, Mönkkönen J -1995-. Effect of liposomal and free bisphosphonates on the IL-1 beta, IL-6 and TNF alpha secretion from RAW 264 cells in vitro. Pharm Res12:916–922.
20.
Pilbeam CC, Harrison JR, Raisz LG -2002-. Prostaglandins and bone metabolism. In: Principles of bone biology. 2nd ed. Vol. 2. Bilezikian JP, Raisz LG, Rodan GA, editors. San Diego: Academic Press, pp. 979–994.
21.
Plosker GL, Goa KL -1994-. Clodronate. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs47:945–982.
22.
Richards PJ, Williams BD, Williams AS -2001-. Suppression of chronic streptococcal cell wall-induced arthritis in Lewis rats by liposomal clodronate. Rheumatology -Oxford-40:978–987.
23.
Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Mönkkönen J, et al. -2000-. Cellular and molecular mechanisms of action of bisphosphonates. Cancer88-12 Suppl-:2961–2978.
24.
Rygh P -1987-. Periodontal response to tooth-moving force: is trauma necessary? In: Orthodontics-state of the art, essence of the science. Graber LW, editor. St. Louis: Mosby, pp. 100–115.
25.
Saito M, Saito S, Ngan PW, Shanfeld J, Davidovitch Z -1991-. Interleukin 1 beta and prostaglandin E are involved in the response of periodontal cells to mechanical stress in vivo and in vitro. Am J Orthod Dentofacial Orthop99:226–240.
26.
Sandy JR, Harris M -1984-. Prostaglandins and tooth movement. Eur J Orthod6:175–182.
27.
Shirazi M, Nilforoushan D, Alghasi H, Dehpour A-R -2002-. The role of nitric oxide in orthodontic tooth movement in rats. Angle Orthod72:211–215.
28.
Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ -1999-. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev20:345–357.
29.
Yamasaki K, Miura F, Suda T -1980-. Prostaglandin as a mediator of bone resorption induced by experimental tooth movement in rats. J Dent Res59:1635–1642.
30.
Zhou D, Hughes B, King GJ -1997-. Histomorphometric and biochemical study of osteoclasts at orthodontic compression sites in the rat during indomethacin inhibition. Arch Oral Biol42:717–726.
