title: Alveolar bone loss: mechanisms, potential therapeutic targets, and interventions.
abstract: This article reviews recent research into mechanisms underlying bone resorption and highlights avenues of investigation that may generate new therapies to combat alveolar bone loss in periodontitis. Several proteins, signaling pathways, stem cells, and dietary supplements are discussed as they relate to periodontal bone loss and regeneration. RGS12 is a crucial protein that mediates osteoclastogenesis and bone destruction, and a potential therapeutic target. RGS12 likely regulates osteoclast differentiation through regulating calcium influx to control the calcium oscillation-NFATc1 pathway. A working model for RGS10 and RGS12 in the regulation of Ca(2+) oscillations during osteoclast differentiation is proposed. Initiation of inflammation depends on host cell-microbe interactions, including the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Oral p38 inhibitors reduced lipopolysaccharide (LPS)-induced bone destruction in a rat periodontitis model but showed unsatisfactory safety profiles. The p38 substrate MK2 is a more specific therapeutic target with potentially superior tolerability. Furthermore, MKP-1 shows anti-inflammatory activity, reducing inflammatory cytokine biosynthesis and bone resorption. Multipotent skeletal stem cell (SSC) populations exist within the bone marrow and periosteum of long bones. These bone-marrow-derived SSCs and periosteum-derived SSCs have shown therapeutic potential in several applications, including bone and periodontal regeneration. The existence of craniofacial bone-specific SSCs is suggested based on existing studies. The effects of calcium, vitamin D, and soy isoflavone supplementation on alveolar and skeletal bone loss in post-menopausal women were investigated. Supplementation resulted in stabilization of forearm bone mass density and a reduced rate of alveolar bone loss over 1 yr, compared with placebo. Periodontal attachment levels were also well-maintained and alveolar bone loss suppressed during 24 wk of supplementation.
authors.affiliation: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, REB 513, Boston, MA 02115, USA.
authors.forename: G
authors.initials: G
authors.lastname: Intini
authors.forename: Y
authors.initials: Y
authors.lastname: Katsuragi
authors.forename: K L
authors.initials: KL
authors.lastname: Kirkwood
authors.forename: S
authors.initials: S
authors.lastname: Yang
mesh_terms: D016301:Alveolar Bone Loss; D001862:Bone Resorption; D002118:Calcium / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007529:Isoflavones / Q000008:administration & dosage*; D008875:Middle Aged; D017698:Postmenopause; D020710:RGS Proteins / Q000502:physiology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D014807:Vitamin D / Q000008:administration & dosage*
chemical_list: D007529:Isoflavones; D020710:RGS Proteins; D014807:Vitamin D; D002118:Calcium
keywords: menopause; mesenchymal stem cells; p38 MAPK; p38 inhibitors; regulator of G protein signaling; skeletal stem cells
references.citation: Nature. 2002 Jul 4;418(6893):41-9
references.pmid: 12077603
references.citation: Stem Cells. 2001;19(3):180-92
references.pmid: 11359943
references.citation: Differentiation. 2007 Jun;75(5):463-77
references.pmid: 17286603
references.citation: Bone. 2004 Nov;35(5):1003-12
references.pmid: 15542024
references.citation: Osteoporos Int. 1994 Mar;4(2):104-9
references.pmid: 8003839
references.citation: Eur J Nutr. 2004 Aug;43(4):246-57
references.pmid: 15309425
references.citation: Biochem Biophys Res Commun. 2009 Aug 28;386(3):477-82
references.pmid: 19538944
references.citation: Am J Pathol. 2006 Sep;169(3):987-98
references.pmid: 16936272
references.citation: J Dent Res. 2009 Dec;88(12):1125-30
references.pmid: 19864641
references.citation: J Intern Med. 2006 Jun;259(6):539-52
references.pmid: 16704554
references.citation: Genes Dev. 2007 Jul 15;21(14):1803-16
references.pmid: 17626792
references.citation: Biomaterials. 2010 Nov;31(33):8574-82
references.pmid: 20832109
references.citation: Development. 2008 Sep;135(17):2845-54
references.pmid: 18653558
references.citation: Biochem Biophys Res Commun. 1989 Sep 29;163(3):1461-5
references.pmid: 2783143
references.citation: PLoS One. 2010 Dec 07;5(12):e14247
references.pmid: 21151872
references.citation: FASEB J. 2006 Dec;20(14):2562-4
references.pmid: 17077282
references.citation: J Biol Chem. 1999 Feb 5;274(6):3549-56
references.pmid: 9920901
references.citation: J Biol Chem. 2001 Apr 27;276(17):13941-8
references.pmid: 11278341
references.citation: Tissue Eng. 2005 Jul-Aug;11(7-8):1198-211
references.pmid: 16144456
references.citation: J Cell Biol. 2001 Jan 8;152(1):181-95
references.pmid: 11149930
references.citation: Oral Microbiol Immunol. 2007 Jun;22(3):208-15
references.pmid: 17488448
references.citation: Arthritis Rheum. 2006 Apr;54(4):1209-21
references.pmid: 16575900
references.citation: J Pharmacol Exp Ther. 2007 Jan;320(1):56-63
references.pmid: 17041006
references.citation: Annu Rev Pharmacol Toxicol. 2000;40:235-71
references.pmid: 10836135
references.citation: Nature. 2000 Dec 7;408(6813):723-7
references.pmid: 11130074
references.citation: Cytokine. 2009 Dec;48(3):161-9
references.pmid: 19740675
references.citation: J Biol Chem. 1998 Dec 25;273(52):34687-90
references.pmid: 9856989
references.citation: Curr Opin Drug Discov Devel. 2005 Jul;8(4):421-30
references.pmid: 16022178
references.citation: Cell Stem Cell. 2012 Mar 2;10(3):259-72
references.pmid: 22385654
references.citation: J Dent Res. 2014 Feb;93(2):109-16
references.pmid: 24088412
references.citation: Stem Cell Rev Rep. 2012 Sep;8(3):882-90
references.pmid: 22622690
references.citation: Nat Genet. 2006 Dec;38(12):1424-9
references.pmid: 17099713
references.citation: Haematologica. 2011 Jul;96(7):1072-6
references.pmid: 21393326
references.citation: Genes Dev. 1995 May 15;9(10):1237-49
references.pmid: 7758948
references.citation: Nature. 1995 Jun 29;375(6534):784-7
references.pmid: 7596410
references.citation: Life Sci. 2003 Dec 5;74(2-3):163-71
references.pmid: 14607243
references.citation: Menopause. 2004 May-Jun;11(3):290-8
references.pmid: 15167308
references.citation: Ann Periodontol. 2001 Dec;6(1):197-208
references.pmid: 11887465
references.citation: Genesis. 2002 Jun;33(2):77-80
references.pmid: 12112875
references.citation: J Signal Transduct. 2012;2012:308943
references.pmid: 22315682
references.citation: J Cell Sci. 2007 Oct 1;120(Pt 19):3362-71
references.pmid: 17881498
references.citation: Menopause. 2004 May-Jun;11(3):246-54
references.pmid: 15167303
references.citation: J Clin Invest. 2013 Jan;123(1):394-404
references.pmid: 23221342
references.citation: FEMS Immunol Med Microbiol. 2002 Sep 6;34(1):45-50
references.pmid: 12208605
references.citation: J Neurosci. 1997 Oct 1;17(19):7252-66
references.pmid: 9295372
references.citation: J Periodontol. 1996 Oct;67(10 Suppl):1076-84
references.pmid: 8910826
references.citation: J Periodontol. 1994 Dec;65(12):1134-8
references.pmid: 7877085
references.citation: J Bone Miner Res. 2007 Jan;22(1):45-54
references.pmid: 17042716
references.citation: Cell Stem Cell. 2013 Jun 6;12(6):689-98
references.pmid: 23746978
references.citation: J Periodontol. 2000 Jul;71(7):1057-66
references.pmid: 10960010
references.citation: J Biol Chem. 2005 Jan 14;280(2):1521-8
references.pmid: 15536086
references.citation: Cell Stem Cell. 2008 Apr 10;2(4):313-9
references.pmid: 18397751
references.citation: Gene Ther. 2011 Apr;18(4):344-53
references.pmid: 21068780
references.citation: J Pharmacol Exp Ther. 2011 Mar;336(3):633-42
references.pmid: 21139061
references.citation: Genesis. 2013 Mar;51(3):201-9
references.pmid: 23349096
references.citation: J Prosthet Dent. 1990 Jan;63(1):86-9
references.pmid: 2295992
references.citation: Curr Biol. 2001 May 1;11(9):R352-5
references.pmid: 11369246
references.citation: Dev Biol. 2002 Jan 1;241(1):106-16
references.pmid: 11784098