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Trigger osteoclast formation and activation: Molecular treatment strategy of delayed tooth eruption
Medical Hypotheses (2007) 69, 1222–1224
http://intl.elsevierhealth.com/journals/mehy
Trigger osteoclast formation and activation: Molecular treatment strategy of delayed tooth eruption Fang Hua 1, Lu Zhang 1, Zhi Chen
*
Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237# Luo Yu Road, Wuhan, Hubei, China Received 5 April 2007; accepted 5 April 2007
Summary Delayed tooth eruption (DTE) is the emergence of a tooth into the oral cavity at a time that delays significantly from norms. It causes a significant impact on a patient’s oral health. Some methods have been suggested to rescue the delayed tooth eruption. However, no approach aims to accelerate the biological process of tooth eruption and rescue these eruption disorders. Recent researches have shown that tooth eruption depends on the presence of osteoclasts to create an eruption pathway through the alveolar bone. We postulate a new approach that targets osteoclast formation and activation to accelerate the eruption of the affected tooth. These strategies include stimulating osteoclastogenesis by applying the cytokines or small molecules, such as TNF-a, IL-1a and MCP-1; triggering osteoclast differentiation by applying molecules associated RANKL signaling, such as RANKL-Fc and OPG antibody; enhancing the function of osteoclasts by applying proteinases, such as CTSK. For the clinical point of view, we can inject these molecules in the oral mucosa of the affected tooth to induce bone resorption, then to rebuild the pathway of tooth eruption. c 2007 Elsevier Ltd. All rights reserved.
Introduction Tooth eruption is the migration of a tooth from its bony crypt within the jaw to the functional position in the dental arch [1]. It is a physiologic process that strongly influences the normal development of the craniofacial complex. Delayed tooth eruption (DTE) is the emergence of a tooth into the oral cavity at a time that delays significantly from * Corresponding author. Tel./fax: +86 27 87873849. E-mail address: [email protected] (Z. Chen). 1 Fang Hua and Lu Zhang contribute equally.
norms [2]. This tooth disorder can directly induce a lot of oral problems, such as occlusion dysfunction, temporo-mandibular joint dysfunction and chewing dysfunction, which can affect psychological health and quality of life in the adulthood. Some reports mentioned that abnormal erupted teeth might cause problems by ankylosis with alveolar bone and the formation of cysts of fistulas [3,4]. Thus, DTE can have a significant impact on a patient’s oral health. Some methods have been suggested to rescue the delayed tooth eruption. These include ‘removing the tooth affected by DTE, elimination of
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.04.012
Trigger osteoclast formation and activation obstacles to eruption, exposure of effected teeth with or without orthodontic traction, and control of the system disease [2,5,6]. To the young patients of DTE, these surgical or orthodontic treatments will increase their pain and mental burden. Furthermore, no approach aims to accelerate the biological process of tooth eruption and rescue this eruption disorder without surgical or orthodontic operation. Various theories regarding the mechanisms of tooth eruption exist. These include root development, changes in the dental pulp, changes in the alveolar bone, and changes in the periapical tissues [7,8]. Now, there are many evidences to implicate that eruption of teeth is critically dependent upon the presence of osteoclasts to create an eruption pathway through the alveolar bone [9]. Mononuclear cells (osteoclast precursors) must be recruited into the dental follicle (DF) prior to the onset of eruption. These cells, in turn, fuse to form osteoclasts and differentiate into mature osteoclasts that resorb alveolar bone, forming an eruption pathway for the tooth to exit its bony crypt. Spontaneous and engineered mice that either lack osteoclasts completely or lack functional osteoclasts lead to severe disturbance of tooth eruption [10]. These facts have demonstrated that this cell type is essential for successful tooth eruption. Many of the genes responsible for osteoclast formation, differentiation and function have been identified. Tumor necrosis factor-alpha (TNF-a), interleukin-one alpha (IL-1a) and monocyte chemotactic protein-1 (MCP-1) are secreted molecules that act as chemokines to recruit mononuclear cells to the DF [9,11]. After the mononuclear cells have been recruited to the DF, there must be a favorable environment within the DF region to promote the fusion of these cells to form osteoclasts. Macrophage colony stimulating factor (M-CSF), receptor activator of nuclear factor kappa B (RANK) and receptor activator of nuclear factor kappa B ligand (RANKL) may be required for this progression of osteoclast differentiation [9,11,12]. Moreover, those genes coding for c-Src, TNF receptor-associated factor 6(TRAF6), tartrateresistant acid phosphatase (TRAP) and cathepsin K (CTSK) affect specifically the function of osteoclasts to resorb alveolar bone [13]. Disruption of these genes blocks the development or function of the mature osteoclasts, resulting in a delay or failure of tooth eruption in rodents [10]. Here, we suppose an approach aims to trigger osteoclasts formation, differentiation and function to rescue DTE without surgical or orthodontic treatments.
1223
The hypothesis Triggering osteoclasts formation and activation might be an effective molecule treatment strategy for delayed tooth eruption.
Implication In general, any strategy to trigger osteoclast formation, differentiation and function will be suitable for treatment of DTE. One strategy is to stimulate osteoclast formation. For the diseases characterized by excessive bone resorption, an important aim of treatments is to limit the progression of bone erosion. Anticytokine therapy, in the form of anti-TNF-a and anti-IL-1 blockade, has provided evidence for its ability to retard bone loss [14,15]. For delayed tooth eruption, the aim is to induce bone erosion on the supposed position. So the first strategy is to stimulate osteoclastogenesis by applying the cytokines or small molecules [16], such as TNF-a, IL-1a and MCP-1, in the local position of the affected tooth. The second strategy is to induce the bone loss by triggering osteoclast differentiation. The concept that cytokine and hormonal factors implicated on bone resorption may act via a common final pathway involving RANKL [17] has suggested the critical role of RANKL signaling in the osteoclast differentiation. Current strategies of the diseases characterized by excessive bone resorption have targeted to block RANKL signaling. A trial of osteoprotegerin (OPG) in postmenopausal women reported that a single injection of OPG-Fc resulted in sustained suppression of bone resorption [18]. The application of RANKL antibody which specially binds to human RANKL in the treatment of rheumatoid arthritis may be of potential benefit [19]. For delayed tooth eruption, we can inject the small molecules associated RANKL signaling, such as RANKL-Fc and OPG antibody in the oral mucosa of the affected tooth to induce the local osteoclast differentiation. The third strategy is to enhance the function of osteoclasts. As we all know, proteinases play important roles in bone physiology not only because they are required for the solubilization of bone matrix, but also because they are key components of the mechanisms that determine where and when bone resorption will be initiated [20]. So we can directly inject proteinases, such as CTSK, in the local position of the affected tooth to induce bone resorption, then to rebuild the pathway of tooth eruption.
1224
Hua et al.
In summary, DTE is a common clinic problem that significantly impacts on patient’s oral health. We suppose a new treatment strategy targets to trigger osteoclasts formation, differentiation and function to rescue DTE without surgical or orthodontic treatments.
References [1] Marks Jr SC, Schroeder HE. Tooth eruption: theories and facts. Anat Rec 1996;245:374–93. [2] Suri L, Gagari E, Vastardis H. Delayed tooth eruption: pathogenesis, diagnosis, and treatment. A literature review. Am J Orthod Dentofacial Orthop 2004;126:432–5. [3] Friede H, Manaligod JR, Rosenthal IM. Craniofacial abnormalities in osteopetrosis with precocious manifestations: report of a case with serial cephalometric roentgenograms. J Craniofac Genet Dev Biol 1985;5:247–57. [4] Reeves J, Arnaud S, Gordon S, et al. The pathogenesis of infantile malignant osteopetrosis: bone mineral metabolism and complications in five infants. Metab Bone Dis Relat Res 1981;3:135–42. [5] Malmgren B, Norgren S. Dental aberrations in children and adolescents with osteogenesis imperfecta. Acta Odontol Scand 2002;60:65–71. [6] O’Connell AC, Puck JM, Grimbacher B, et al. Delayed eruption of permanent teeth in hyperimmunoglobulinemia E recurrent infection syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:177–85. [7] Craddock HL, Youngson GG. Eruptive tooth movement – the current state of knowledge. Br Dent J 2004;197: 385–91. [8] Sutton PR, Graze HR. The blood-vessel thrust theory of tooth eruption and migration. Med Hypotheses 1985;18:289–95.
[9] Wise GE, Frazier-Bowers S, D’Souza RN. Cellular, molecular, and genetic determinants of tooth eruption. Crit Rev Oral Biol Med 2002;13:323–4. [10] Helfrich MH. Osteoclast diseases and dental abnormalities. Arch Oral Biol 2005;50:115–22. [11] Wise GE, Huang H, Que BG. Gene expression of potential tooth eruption molecules in the dental follicle of the mouse. Eur J Oral Sci 1999;107:482–6. [12] Que BG, Lumpkin SJ, Wise GE. Implications for tooth eruption of the effect of interleukin-1alpha on nuclear factor-kappa B gene expression in the rat dental follicle. J Dent Res 1999;78:1677–81. [13] Helfrich MH. Osteoclast diseases. Microsc Res Tech 2003;61:514–32. [14] Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum 2004;50:2264–72. [15] Antoni CE, Kavanaugh A, Kirkham B. Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial. Arthritis Rheum 2005;52:1227–36. [16] Zhang L, Sun ZJ, Zhao YF, et al. Inhibition of SHH signaling pathway: molecular treatment strategy of odontogenic keratocyst. Med Hypotheses 2006;67:1242–4. [17] Anandarajah AP, Schwarz EM. Anti-RANKL therapy for inflammatory bone disorders: mechanisms and potential clinical applications. J Cell Biochem 2006;97:226–32. [18] Bekker PJ, Holloway D, Nakanishi A, et al. Osteoprotegerin (OPG) has potent and sustained antiresorptive activity in postmenopausal women. J Bone Miner Res 2001;16:348–60. [19] Lewiecki EM. RANK ligand inhibition with denosumab for the management of osteoporosis. Expert Opin Boil Ther 2006;6:1041–50. [20] Wittrant Y, Theoleyre S, Couillaud S, et al. Regulation of osteoclast protease expression by RANKL. Biochem Biophys Res Commun 2003;310:774–8.
Available online at www.sciencedirect.com
http://intl.elsevierhealth.com/journals/mehy
Trigger osteoclast formation and activation: Molecular treatment strategy of delayed tooth eruption Fang Hua 1, Lu Zhang 1, Zhi Chen
*
Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237# Luo Yu Road, Wuhan, Hubei, China Received 5 April 2007; accepted 5 April 2007
Summary Delayed tooth eruption (DTE) is the emergence of a tooth into the oral cavity at a time that delays significantly from norms. It causes a significant impact on a patient’s oral health. Some methods have been suggested to rescue the delayed tooth eruption. However, no approach aims to accelerate the biological process of tooth eruption and rescue these eruption disorders. Recent researches have shown that tooth eruption depends on the presence of osteoclasts to create an eruption pathway through the alveolar bone. We postulate a new approach that targets osteoclast formation and activation to accelerate the eruption of the affected tooth. These strategies include stimulating osteoclastogenesis by applying the cytokines or small molecules, such as TNF-a, IL-1a and MCP-1; triggering osteoclast differentiation by applying molecules associated RANKL signaling, such as RANKL-Fc and OPG antibody; enhancing the function of osteoclasts by applying proteinases, such as CTSK. For the clinical point of view, we can inject these molecules in the oral mucosa of the affected tooth to induce bone resorption, then to rebuild the pathway of tooth eruption. c 2007 Elsevier Ltd. All rights reserved.
Introduction Tooth eruption is the migration of a tooth from its bony crypt within the jaw to the functional position in the dental arch [1]. It is a physiologic process that strongly influences the normal development of the craniofacial complex. Delayed tooth eruption (DTE) is the emergence of a tooth into the oral cavity at a time that delays significantly from * Corresponding author. Tel./fax: +86 27 87873849. E-mail address: [email protected] (Z. Chen). 1 Fang Hua and Lu Zhang contribute equally.
norms [2]. This tooth disorder can directly induce a lot of oral problems, such as occlusion dysfunction, temporo-mandibular joint dysfunction and chewing dysfunction, which can affect psychological health and quality of life in the adulthood. Some reports mentioned that abnormal erupted teeth might cause problems by ankylosis with alveolar bone and the formation of cysts of fistulas [3,4]. Thus, DTE can have a significant impact on a patient’s oral health. Some methods have been suggested to rescue the delayed tooth eruption. These include ‘removing the tooth affected by DTE, elimination of
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.04.012
Trigger osteoclast formation and activation obstacles to eruption, exposure of effected teeth with or without orthodontic traction, and control of the system disease [2,5,6]. To the young patients of DTE, these surgical or orthodontic treatments will increase their pain and mental burden. Furthermore, no approach aims to accelerate the biological process of tooth eruption and rescue this eruption disorder without surgical or orthodontic operation. Various theories regarding the mechanisms of tooth eruption exist. These include root development, changes in the dental pulp, changes in the alveolar bone, and changes in the periapical tissues [7,8]. Now, there are many evidences to implicate that eruption of teeth is critically dependent upon the presence of osteoclasts to create an eruption pathway through the alveolar bone [9]. Mononuclear cells (osteoclast precursors) must be recruited into the dental follicle (DF) prior to the onset of eruption. These cells, in turn, fuse to form osteoclasts and differentiate into mature osteoclasts that resorb alveolar bone, forming an eruption pathway for the tooth to exit its bony crypt. Spontaneous and engineered mice that either lack osteoclasts completely or lack functional osteoclasts lead to severe disturbance of tooth eruption [10]. These facts have demonstrated that this cell type is essential for successful tooth eruption. Many of the genes responsible for osteoclast formation, differentiation and function have been identified. Tumor necrosis factor-alpha (TNF-a), interleukin-one alpha (IL-1a) and monocyte chemotactic protein-1 (MCP-1) are secreted molecules that act as chemokines to recruit mononuclear cells to the DF [9,11]. After the mononuclear cells have been recruited to the DF, there must be a favorable environment within the DF region to promote the fusion of these cells to form osteoclasts. Macrophage colony stimulating factor (M-CSF), receptor activator of nuclear factor kappa B (RANK) and receptor activator of nuclear factor kappa B ligand (RANKL) may be required for this progression of osteoclast differentiation [9,11,12]. Moreover, those genes coding for c-Src, TNF receptor-associated factor 6(TRAF6), tartrateresistant acid phosphatase (TRAP) and cathepsin K (CTSK) affect specifically the function of osteoclasts to resorb alveolar bone [13]. Disruption of these genes blocks the development or function of the mature osteoclasts, resulting in a delay or failure of tooth eruption in rodents [10]. Here, we suppose an approach aims to trigger osteoclasts formation, differentiation and function to rescue DTE without surgical or orthodontic treatments.
1223
The hypothesis Triggering osteoclasts formation and activation might be an effective molecule treatment strategy for delayed tooth eruption.
Implication In general, any strategy to trigger osteoclast formation, differentiation and function will be suitable for treatment of DTE. One strategy is to stimulate osteoclast formation. For the diseases characterized by excessive bone resorption, an important aim of treatments is to limit the progression of bone erosion. Anticytokine therapy, in the form of anti-TNF-a and anti-IL-1 blockade, has provided evidence for its ability to retard bone loss [14,15]. For delayed tooth eruption, the aim is to induce bone erosion on the supposed position. So the first strategy is to stimulate osteoclastogenesis by applying the cytokines or small molecules [16], such as TNF-a, IL-1a and MCP-1, in the local position of the affected tooth. The second strategy is to induce the bone loss by triggering osteoclast differentiation. The concept that cytokine and hormonal factors implicated on bone resorption may act via a common final pathway involving RANKL [17] has suggested the critical role of RANKL signaling in the osteoclast differentiation. Current strategies of the diseases characterized by excessive bone resorption have targeted to block RANKL signaling. A trial of osteoprotegerin (OPG) in postmenopausal women reported that a single injection of OPG-Fc resulted in sustained suppression of bone resorption [18]. The application of RANKL antibody which specially binds to human RANKL in the treatment of rheumatoid arthritis may be of potential benefit [19]. For delayed tooth eruption, we can inject the small molecules associated RANKL signaling, such as RANKL-Fc and OPG antibody in the oral mucosa of the affected tooth to induce the local osteoclast differentiation. The third strategy is to enhance the function of osteoclasts. As we all know, proteinases play important roles in bone physiology not only because they are required for the solubilization of bone matrix, but also because they are key components of the mechanisms that determine where and when bone resorption will be initiated [20]. So we can directly inject proteinases, such as CTSK, in the local position of the affected tooth to induce bone resorption, then to rebuild the pathway of tooth eruption.
1224
Hua et al.
In summary, DTE is a common clinic problem that significantly impacts on patient’s oral health. We suppose a new treatment strategy targets to trigger osteoclasts formation, differentiation and function to rescue DTE without surgical or orthodontic treatments.
References [1] Marks Jr SC, Schroeder HE. Tooth eruption: theories and facts. Anat Rec 1996;245:374–93. [2] Suri L, Gagari E, Vastardis H. Delayed tooth eruption: pathogenesis, diagnosis, and treatment. A literature review. Am J Orthod Dentofacial Orthop 2004;126:432–5. [3] Friede H, Manaligod JR, Rosenthal IM. Craniofacial abnormalities in osteopetrosis with precocious manifestations: report of a case with serial cephalometric roentgenograms. J Craniofac Genet Dev Biol 1985;5:247–57. [4] Reeves J, Arnaud S, Gordon S, et al. The pathogenesis of infantile malignant osteopetrosis: bone mineral metabolism and complications in five infants. Metab Bone Dis Relat Res 1981;3:135–42. [5] Malmgren B, Norgren S. Dental aberrations in children and adolescents with osteogenesis imperfecta. Acta Odontol Scand 2002;60:65–71. [6] O’Connell AC, Puck JM, Grimbacher B, et al. Delayed eruption of permanent teeth in hyperimmunoglobulinemia E recurrent infection syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:177–85. [7] Craddock HL, Youngson GG. Eruptive tooth movement – the current state of knowledge. Br Dent J 2004;197: 385–91. [8] Sutton PR, Graze HR. The blood-vessel thrust theory of tooth eruption and migration. Med Hypotheses 1985;18:289–95.
[9] Wise GE, Frazier-Bowers S, D’Souza RN. Cellular, molecular, and genetic determinants of tooth eruption. Crit Rev Oral Biol Med 2002;13:323–4. [10] Helfrich MH. Osteoclast diseases and dental abnormalities. Arch Oral Biol 2005;50:115–22. [11] Wise GE, Huang H, Que BG. Gene expression of potential tooth eruption molecules in the dental follicle of the mouse. Eur J Oral Sci 1999;107:482–6. [12] Que BG, Lumpkin SJ, Wise GE. Implications for tooth eruption of the effect of interleukin-1alpha on nuclear factor-kappa B gene expression in the rat dental follicle. J Dent Res 1999;78:1677–81. [13] Helfrich MH. Osteoclast diseases. Microsc Res Tech 2003;61:514–32. [14] Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum 2004;50:2264–72. [15] Antoni CE, Kavanaugh A, Kirkham B. Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial. Arthritis Rheum 2005;52:1227–36. [16] Zhang L, Sun ZJ, Zhao YF, et al. Inhibition of SHH signaling pathway: molecular treatment strategy of odontogenic keratocyst. Med Hypotheses 2006;67:1242–4. [17] Anandarajah AP, Schwarz EM. Anti-RANKL therapy for inflammatory bone disorders: mechanisms and potential clinical applications. J Cell Biochem 2006;97:226–32. [18] Bekker PJ, Holloway D, Nakanishi A, et al. Osteoprotegerin (OPG) has potent and sustained antiresorptive activity in postmenopausal women. J Bone Miner Res 2001;16:348–60. [19] Lewiecki EM. RANK ligand inhibition with denosumab for the management of osteoporosis. Expert Opin Boil Ther 2006;6:1041–50. [20] Wittrant Y, Theoleyre S, Couillaud S, et al. Regulation of osteoclast protease expression by RANKL. Biochem Biophys Res Commun 2003;310:774–8.
Available online at www.sciencedirect.com