Local simvastatin effects on mandibular bone growth and inflammation

David Stein, Yeonju Lee, Marian J. Schmid, Byron Killpack, Mikala A. Genrich, Nagamani Narayana, David B. Marx, Diane M. Cullen, Richard A Reinhardt

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

Background: Simvastatin has been shown to increase bone growth when applied topically to murine bone; however, it causes considerable soft tissue inflammation at high doses (2.2 mg), making future clinical use problematic. This study evaluated the effect of lower simvastatin doses and cyclooxygenase (COX) synthase inhibitors on tissue inflammation and bone growth in rats and gene expression in mice. Methods: Adult female rats were untreated or treated with a single dose of 0.1, 0.5, 1.0, 1.5, or 2.2 mg simvastatin in methylcellulose gel in a polylactic acid membrane (SIM) on the lateral aspect of the mandible. The contralateral mandible side was implanted with methylcellulose gel/polylactic acid membrane alone (GEL), and five rats in each dose pairing were evaluated histomorphometrically after 3, 7, and 24 days. Subsequent rats were similarly treated with 0.5 mg simvastatin (optimal dose) and daily intraperitoneal injections of COX-2 inhibitor (NS-398; 1 mg/kg × 7 days; N = 16), general COX inhibitor (indomethacin; 1 mg/kg × 7 days; N = 16), or no inhibitor (N = 10) and evaluated histomorphometrically after 7 or 24 days by analysis of variance (ANOVA). Gene arrays were also used to evaluate osteogenic gene expression from 0.5 mg simvastatin in murine calvaria (N = 12). Results: There was a 45% increase in bone area with 0.5 mg simvastatin versus gel control (P <0.001; similar to the 2.2-mg dose), and clinical swelling was reduced compared to the high simvastatin dose (P <0.05). The 0.1-mg simvastatin dose failed to stimulate significant bone growth. NS-398 and indomethacin reduced inflammation and bone growth. Simvastatin significantly upregulated procollagen, fibronectin, and matrix metalloproteinase-13 genes. Conclusion: Reducing the simvastatin dose from 2.2 to 0.5 mg reduced inflammation to a more clinically acceptable level without sacrificing bone-growth potential, but COX-associated inflammation appears to be necessary for in vivo bone growth.

Original languageEnglish (US)
Pages (from-to)1861-1870
Number of pages10
JournalJournal of periodontology
Volume76
Issue number11
DOIs
StatePublished - Nov 1 2005

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Osteitis
Simvastatin
Bone Development
Inflammation
Methylcellulose
Cyclooxygenase Inhibitors
Gels
Mandible
Indomethacin
Matrix Metalloproteinase 13
Gene Expression
Bone and Bones
Procollagen
Membranes
Cyclooxygenase 2 Inhibitors
Prostaglandin-Endoperoxide Synthases
Intraperitoneal Injections
Fibronectins
Skull
Genes

Keywords

  • Histology
  • Mandible
  • Mice
  • Osteogenic genes
  • Rats

ASJC Scopus subject areas

  • Periodontics

Cite this

Local simvastatin effects on mandibular bone growth and inflammation. / Stein, David; Lee, Yeonju; Schmid, Marian J.; Killpack, Byron; Genrich, Mikala A.; Narayana, Nagamani; Marx, David B.; Cullen, Diane M.; Reinhardt, Richard A.

In: Journal of periodontology, Vol. 76, No. 11, 01.11.2005, p. 1861-1870.

Research output: Contribution to journalArticle

Stein, D, Lee, Y, Schmid, MJ, Killpack, B, Genrich, MA, Narayana, N, Marx, DB, Cullen, DM & Reinhardt, RA 2005, 'Local simvastatin effects on mandibular bone growth and inflammation', Journal of periodontology, vol. 76, no. 11, pp. 1861-1870. https://doi.org/10.1902/jop.2005.76.11.1861
Stein, David ; Lee, Yeonju ; Schmid, Marian J. ; Killpack, Byron ; Genrich, Mikala A. ; Narayana, Nagamani ; Marx, David B. ; Cullen, Diane M. ; Reinhardt, Richard A. / Local simvastatin effects on mandibular bone growth and inflammation. In: Journal of periodontology. 2005 ; Vol. 76, No. 11. pp. 1861-1870.
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abstract = "Background: Simvastatin has been shown to increase bone growth when applied topically to murine bone; however, it causes considerable soft tissue inflammation at high doses (2.2 mg), making future clinical use problematic. This study evaluated the effect of lower simvastatin doses and cyclooxygenase (COX) synthase inhibitors on tissue inflammation and bone growth in rats and gene expression in mice. Methods: Adult female rats were untreated or treated with a single dose of 0.1, 0.5, 1.0, 1.5, or 2.2 mg simvastatin in methylcellulose gel in a polylactic acid membrane (SIM) on the lateral aspect of the mandible. The contralateral mandible side was implanted with methylcellulose gel/polylactic acid membrane alone (GEL), and five rats in each dose pairing were evaluated histomorphometrically after 3, 7, and 24 days. Subsequent rats were similarly treated with 0.5 mg simvastatin (optimal dose) and daily intraperitoneal injections of COX-2 inhibitor (NS-398; 1 mg/kg × 7 days; N = 16), general COX inhibitor (indomethacin; 1 mg/kg × 7 days; N = 16), or no inhibitor (N = 10) and evaluated histomorphometrically after 7 or 24 days by analysis of variance (ANOVA). Gene arrays were also used to evaluate osteogenic gene expression from 0.5 mg simvastatin in murine calvaria (N = 12). Results: There was a 45{\%} increase in bone area with 0.5 mg simvastatin versus gel control (P <0.001; similar to the 2.2-mg dose), and clinical swelling was reduced compared to the high simvastatin dose (P <0.05). The 0.1-mg simvastatin dose failed to stimulate significant bone growth. NS-398 and indomethacin reduced inflammation and bone growth. Simvastatin significantly upregulated procollagen, fibronectin, and matrix metalloproteinase-13 genes. Conclusion: Reducing the simvastatin dose from 2.2 to 0.5 mg reduced inflammation to a more clinically acceptable level without sacrificing bone-growth potential, but COX-associated inflammation appears to be necessary for in vivo bone growth.",
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AU - Narayana, Nagamani

AU - Marx, David B.

AU - Cullen, Diane M.

AU - Reinhardt, Richard A

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N2 - Background: Simvastatin has been shown to increase bone growth when applied topically to murine bone; however, it causes considerable soft tissue inflammation at high doses (2.2 mg), making future clinical use problematic. This study evaluated the effect of lower simvastatin doses and cyclooxygenase (COX) synthase inhibitors on tissue inflammation and bone growth in rats and gene expression in mice. Methods: Adult female rats were untreated or treated with a single dose of 0.1, 0.5, 1.0, 1.5, or 2.2 mg simvastatin in methylcellulose gel in a polylactic acid membrane (SIM) on the lateral aspect of the mandible. The contralateral mandible side was implanted with methylcellulose gel/polylactic acid membrane alone (GEL), and five rats in each dose pairing were evaluated histomorphometrically after 3, 7, and 24 days. Subsequent rats were similarly treated with 0.5 mg simvastatin (optimal dose) and daily intraperitoneal injections of COX-2 inhibitor (NS-398; 1 mg/kg × 7 days; N = 16), general COX inhibitor (indomethacin; 1 mg/kg × 7 days; N = 16), or no inhibitor (N = 10) and evaluated histomorphometrically after 7 or 24 days by analysis of variance (ANOVA). Gene arrays were also used to evaluate osteogenic gene expression from 0.5 mg simvastatin in murine calvaria (N = 12). Results: There was a 45% increase in bone area with 0.5 mg simvastatin versus gel control (P <0.001; similar to the 2.2-mg dose), and clinical swelling was reduced compared to the high simvastatin dose (P <0.05). The 0.1-mg simvastatin dose failed to stimulate significant bone growth. NS-398 and indomethacin reduced inflammation and bone growth. Simvastatin significantly upregulated procollagen, fibronectin, and matrix metalloproteinase-13 genes. Conclusion: Reducing the simvastatin dose from 2.2 to 0.5 mg reduced inflammation to a more clinically acceptable level without sacrificing bone-growth potential, but COX-associated inflammation appears to be necessary for in vivo bone growth.

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