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Local lipopolysaccharide injection: A potential novel treatment for heterotopic ossification
Medical Hypotheses 74 (2010) 330–331
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Local lipopolysaccharide injection: A potential novel treatment for heterotopic ossification De-Ting Xue, Qiang Zheng, Hang Li, Zhi-Jun Pan * Department of Orthopaedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, PR China
a r t i c l e
i n f o
Article history: Received 17 August 2009 Accepted 23 August 2009
s u m m a r y Heterotopic ossification (HO) is a frequent complication after musculoskeletal trauma and surgical procedures. It usually decreases joint mobility and eventually causes loss of joint function. However, there is no satisfied treatment available for HO. Lipopolysaccharide (LPS) is traditionally recognized as an endotoxin. Recently, studies found LPS was associated with loss of bone during bacterial infection and periprosthetic osteolysis after total joint replacement. Cell and molecular biology studies further found that LPS initiated the osteoclast formation, stimulated osteoclast activity and inhibited osteoblast differentiation. Given HO is an abnormality in bone modeling which increases bone mass within extraskeletal soft tissues, we herein hypothesize that local LPS injection might be a potential novel treatment for HO. Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
Introduction Heterotopic ossification (HO) is a disease of abnormal bone formation within extraskeletal soft tissues. It is a frequent complication after musculoskeletal trauma and surgical procedures such as hip or elbow arthroplasty, fractures, joint dislocations, soft tissue trauma, and spinal cord or central nervous system injury [1–5]. HO often begins as a painful, gradually decreases joint mobility, and eventually causes loss of joint function [6]. However, the exact etiology of HO is still unclear. At present, the prevention and treatments of HO are based mainly on radiotherapy, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids and bisphosphonates, but the results are always not satisfied [7,8]. A study of 10,000 patients with total hip replacement indicted that more than half had radiological evidence of HO, and of these 15% were symptomatic [9]. Once HO develops to interfere significantly with the functional capacity of the patient, the only treatment option remaining is surgery. So finding a novel effective nonsurgical treatment for heterotopic ossification seems quite important. Recently, the possibility that localised bacterial infections contributes to loss of bone has received considerable attention [10]. Some researchers also pointed out that lipopolysaccharide (LPS), the classic endotoxin produced by Gram-negative bacteria, was associated with periprosthetic osteolysis after total joint replacements [11,12]. However, to date, the treatment effect of LPS on HO is still less well known. Given the LPS is possibly associated with loss of bone and HO is mainly due to abnormal bone forma-
* Corresponding author. Address: Department of Orthopaedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, #88, Jiefang Road, Hangzhou 310009, PR China. Tel.: +86 571 8776 7023; fax: +86 571 8702 2776. E-mail address: [email protected] (Z.-J. Pan).
tion, we hypothesize that local LPS injection might be a novel treatment for HO.
Evidences and possible mechanisms LPS is the major component of the Gram-negative bacterial cell wall. It is traditionally recognized as an endotoxin which induces a strong response from normal animal immune systems. Recent years, LPS was shown to be a potent inducer of bone loss in rat models [13]. Peek et al. [14] found that a higher concentration of LPS in cholesteatoma (a disease associated with imbalance between bone formation and resorption) samples from patients with clinical evidence of bone resorption. Greenfield et al. [12] also found that LPS was associated with aseptic loosening of orthopedic implants, which is mainly due to osteolysis. Although the pathogenesis is not clear, LPS may play an important role in bone destruction. From cell and molecular biology aspects, in co-cultures of primary osteoblasts with bone-marrow derived haematopoietic cells, LPS initiated the osteoclast formation and stimulated osteoclast activity [15,16]. LPS could trigger fibroblasts, macrophages, and other cells to produce cytokines, such as TNF-a, which induced osteoclast formation and activation [17,18]. In addition through TNF-a, LPS was reported to enhance osteoclast survival through toll-like receptor 4 (TLR-4) [19]. Some studies further suggested that NF-jB activation seemed to be essential for LPS-induced osteoclastogenesis [20,21]. Besides, Thammasitboon et al. [22] pointed out that LPS inhibited osteoblast differentiation and bone formation. So LPS plays an important role in disrupting the balance between bone formation and resorption by affecting both osteoclast and osteoblast.
0306-9877/$ - see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.08.038
D.-T. Xue et al. / Medical Hypotheses 74 (2010) 330–331
Bone is a dynamic organ constantly being remodeled to achieve both calcium homeostasis and structural integrity through osteoclasts and osteoblasts. HO as an abnormality in bone modeling leads to increased bone mass within extraskeletal soft tissues. Can we reverse this abnormal modeling process? Based on above, we may use LPS to disrupt this abnormal process and induce osteolysis of heterotopic bone mass for treating HO. Our strategy Recently, with the development of material science, injectable biodegradable controlled drug delivery biomaterials make it possible for minimally invasive therapies [23]. So to test this hypothesis, we may encapsulate LPS into injectable biodegradable biomaterials such as collagen or chitosan [24,25], and inject this LPS/biomaterials composite into the region surrounding heterotopic bone mass even endosteal injection to induce osteolysis. Conclusion Theoretical consideration suggested that local injectable biodegradable biomaterials encapsulated LPS injection could induce osteolysis of heterotopic bone mass. If our hypothesis is supported by further experiments, local LPS injection will be a novel treatment for HO without surgical resection. Conflicts of interest statement None declared. References [1] Nilsson OS, Persson PE. Heterotopic bone formation after joint replacement. Curr Opin Rheumatol 1999;11:127–31. [2] Mills WJ, Tejwani N. Heterotopic ossification after knee dislocation: the predictive value of the injury severity score. J Orthop Trauma 2003;17:338–45. [3] Hait G, Boswick Jr JA, Stone NH. Heterotopic bone formation secondary to trauma (myositis ossificans traumatica). J Trauma 1970;10:405–11. [4] Gunduz B, Erhan B, Demir Y. Subcutaneous injections as a risk factor of myositis ossificans traumatica in spinal cord injury. Int J Rehabil Res 2007;30:87–90. [5] Moore TJ. Functional outcome following surgical excision of heterotopic ossification in patients with traumatic brain injury. J Orthop Trauma 1993;7:11–4. [6] Board TN, Karva A, Board RE, Gambhir AK, Porter ML. The prophylaxis and treatment of heterotopic ossification following lower limb arthroplasty. J Bone Joint Surg Br 2007;89:434–40.
331
[7] Healy WL, Lo TC, DeSimone AA, Rask B, Pfeifer BA. Single-dose irradiation for the prevention of heterotopic ossification after total hip arthroplasty. A comparison of doses of five hundred and fifty and seven hundred centigray. J Bone Joint Surg Am 1995;77:590–5. [8] Fijn R, Koorevaar RT, Brouwers JR. Prevention of heterotopic ossification after total hip replacement with NSAIDs. Pharm World Sci 2003;25:138–45. [9] Ahrengart L. Periarticular heterotopic ossification after total hip arthroplasty risk factors and consequences. Clin Orthop Relat Res 1991:49–58. [10] Mormann M, Thederan M, Nackchbandi I, et al. Lipopolysaccharides (LPS) induce the differentiation of human monocytes to osteoclasts in a tumour necrosis factor (TNF) alpha-dependent manner: a link between infection and pathological bone resorption. Mol Immunol 2008;45:3330–7. [11] Cho DR, Shanbhag AS, Hong CY, Baran GR, Goldring SR. The role of adsorbed endotoxin in particle-induced stimulation of cytokine release. J Orthop Res 2002;20:704–13. [12] Greenfield EM, Bi Y, Ragab AA, et al. Does endotoxin contribute to aseptic loosening of orthopedic implants? J Biomed Mater Res B Appl Biomater 2005;72:179–85. [13] Orcel P, Feuga M, Bielakoff J, De Vernejoul MC. Local bone injections of LPS and M-CSF increase bone resorption by different pathways in vivo in rats. Am J Physiol 1993;264:E391–7. [14] Peek FA, Huisman MA, Berckmans RJ, et al. Lipopolysaccharide concentration and bone resorption in cholesteatoma. Otol Neurotol 2003;24:709–13. [15] Islam S, Hassan F, Tumurkhuu G, et al. Bacterial lipopolysaccharide induces osteoclast formation in RAW 264.7 macrophage cells. Biochem Biophys Res Commun 2007;360:346–51. [16] Dumitrescu AL, Abd-El-Aleem S, Morales-Aza B, Donaldson LF. A model of periodontitis in the rat: effect of lipopolysaccharide on bone resorption, osteoclast activity, and local peptidergic innervation. J Clin Periodontol 2004;31:596–603. [17] Shuto T, Jimi E, Kukita T, Hirata M, Koga T. Granulocyte-macrophage colony stimulating factor suppresses lipopolysaccharide-induced osteoclastlike cell formation in mouse bone marrow cultures. Endocrinology 1994;134:831–7. [18] Abu-Amer Y, Ross FP, Edwards J, Teitelbaum SL. Lipopolysaccharidestimulated osteoclastogenesis is mediated by tumor necrosis factor via its P55 receptor. J Clin Invest 1997;100:1557–65. [19] Takami M, Kim N, Rho J, Choi Y. Stimulation by toll-like receptors inhibits osteoclast differentiation. J Immunol 2002;169:1516–23. [20] Miyazaki T, Katagiri H, Kanegae Y, et al. Reciprocal role of ERK and NF-kappaB pathways in survival and activation of osteoclasts. J Cell Biol 2000;148:333–42. [21] Itoh K, Udagawa N, Katagiri T, et al. Bone morphogenetic protein 2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-kappaB ligand. Endocrinology 2001;142:3656–62. [22] Thammasitboon K, Goldring SR, Boch JA. Role of macrophages in LPS-induced osteoblast and PDL cell apoptosis. Bone 2006;38:845–52. [23] Zhang L, Schwendeman SP. Injectable biodegradable polymer depots for minimally invasive delivery of peptides and proteins. Adv Exp Med Biol 2009;611:611–3. [24] Taguchi T, Xu L, Kobayashi H, et al. Encapsulation of chondrocytes in injectable alkali-treated collagen gels prepared using poly(ethylene glycol)-based 4armed star polymer. Biomaterials 2005;26:1247–52. [25] Fujita M, Ishihara M, Simizu M, et al. Vascularization in vivo caused by the controlled release of fibroblast growth factor-2 from an injectable chitosan/ non-anticoagulant heparin hydrogel. Biomaterials 2004;25:699–706.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Local lipopolysaccharide injection: A potential novel treatment for heterotopic ossification De-Ting Xue, Qiang Zheng, Hang Li, Zhi-Jun Pan * Department of Orthopaedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, PR China
a r t i c l e
i n f o
Article history: Received 17 August 2009 Accepted 23 August 2009
s u m m a r y Heterotopic ossification (HO) is a frequent complication after musculoskeletal trauma and surgical procedures. It usually decreases joint mobility and eventually causes loss of joint function. However, there is no satisfied treatment available for HO. Lipopolysaccharide (LPS) is traditionally recognized as an endotoxin. Recently, studies found LPS was associated with loss of bone during bacterial infection and periprosthetic osteolysis after total joint replacement. Cell and molecular biology studies further found that LPS initiated the osteoclast formation, stimulated osteoclast activity and inhibited osteoblast differentiation. Given HO is an abnormality in bone modeling which increases bone mass within extraskeletal soft tissues, we herein hypothesize that local LPS injection might be a potential novel treatment for HO. Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
Introduction Heterotopic ossification (HO) is a disease of abnormal bone formation within extraskeletal soft tissues. It is a frequent complication after musculoskeletal trauma and surgical procedures such as hip or elbow arthroplasty, fractures, joint dislocations, soft tissue trauma, and spinal cord or central nervous system injury [1–5]. HO often begins as a painful, gradually decreases joint mobility, and eventually causes loss of joint function [6]. However, the exact etiology of HO is still unclear. At present, the prevention and treatments of HO are based mainly on radiotherapy, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids and bisphosphonates, but the results are always not satisfied [7,8]. A study of 10,000 patients with total hip replacement indicted that more than half had radiological evidence of HO, and of these 15% were symptomatic [9]. Once HO develops to interfere significantly with the functional capacity of the patient, the only treatment option remaining is surgery. So finding a novel effective nonsurgical treatment for heterotopic ossification seems quite important. Recently, the possibility that localised bacterial infections contributes to loss of bone has received considerable attention [10]. Some researchers also pointed out that lipopolysaccharide (LPS), the classic endotoxin produced by Gram-negative bacteria, was associated with periprosthetic osteolysis after total joint replacements [11,12]. However, to date, the treatment effect of LPS on HO is still less well known. Given the LPS is possibly associated with loss of bone and HO is mainly due to abnormal bone forma-
* Corresponding author. Address: Department of Orthopaedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, #88, Jiefang Road, Hangzhou 310009, PR China. Tel.: +86 571 8776 7023; fax: +86 571 8702 2776. E-mail address: [email protected] (Z.-J. Pan).
tion, we hypothesize that local LPS injection might be a novel treatment for HO.
Evidences and possible mechanisms LPS is the major component of the Gram-negative bacterial cell wall. It is traditionally recognized as an endotoxin which induces a strong response from normal animal immune systems. Recent years, LPS was shown to be a potent inducer of bone loss in rat models [13]. Peek et al. [14] found that a higher concentration of LPS in cholesteatoma (a disease associated with imbalance between bone formation and resorption) samples from patients with clinical evidence of bone resorption. Greenfield et al. [12] also found that LPS was associated with aseptic loosening of orthopedic implants, which is mainly due to osteolysis. Although the pathogenesis is not clear, LPS may play an important role in bone destruction. From cell and molecular biology aspects, in co-cultures of primary osteoblasts with bone-marrow derived haematopoietic cells, LPS initiated the osteoclast formation and stimulated osteoclast activity [15,16]. LPS could trigger fibroblasts, macrophages, and other cells to produce cytokines, such as TNF-a, which induced osteoclast formation and activation [17,18]. In addition through TNF-a, LPS was reported to enhance osteoclast survival through toll-like receptor 4 (TLR-4) [19]. Some studies further suggested that NF-jB activation seemed to be essential for LPS-induced osteoclastogenesis [20,21]. Besides, Thammasitboon et al. [22] pointed out that LPS inhibited osteoblast differentiation and bone formation. So LPS plays an important role in disrupting the balance between bone formation and resorption by affecting both osteoclast and osteoblast.
0306-9877/$ - see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.08.038
D.-T. Xue et al. / Medical Hypotheses 74 (2010) 330–331
Bone is a dynamic organ constantly being remodeled to achieve both calcium homeostasis and structural integrity through osteoclasts and osteoblasts. HO as an abnormality in bone modeling leads to increased bone mass within extraskeletal soft tissues. Can we reverse this abnormal modeling process? Based on above, we may use LPS to disrupt this abnormal process and induce osteolysis of heterotopic bone mass for treating HO. Our strategy Recently, with the development of material science, injectable biodegradable controlled drug delivery biomaterials make it possible for minimally invasive therapies [23]. So to test this hypothesis, we may encapsulate LPS into injectable biodegradable biomaterials such as collagen or chitosan [24,25], and inject this LPS/biomaterials composite into the region surrounding heterotopic bone mass even endosteal injection to induce osteolysis. Conclusion Theoretical consideration suggested that local injectable biodegradable biomaterials encapsulated LPS injection could induce osteolysis of heterotopic bone mass. If our hypothesis is supported by further experiments, local LPS injection will be a novel treatment for HO without surgical resection. Conflicts of interest statement None declared. References [1] Nilsson OS, Persson PE. Heterotopic bone formation after joint replacement. Curr Opin Rheumatol 1999;11:127–31. [2] Mills WJ, Tejwani N. Heterotopic ossification after knee dislocation: the predictive value of the injury severity score. J Orthop Trauma 2003;17:338–45. [3] Hait G, Boswick Jr JA, Stone NH. Heterotopic bone formation secondary to trauma (myositis ossificans traumatica). J Trauma 1970;10:405–11. [4] Gunduz B, Erhan B, Demir Y. Subcutaneous injections as a risk factor of myositis ossificans traumatica in spinal cord injury. Int J Rehabil Res 2007;30:87–90. [5] Moore TJ. Functional outcome following surgical excision of heterotopic ossification in patients with traumatic brain injury. J Orthop Trauma 1993;7:11–4. [6] Board TN, Karva A, Board RE, Gambhir AK, Porter ML. The prophylaxis and treatment of heterotopic ossification following lower limb arthroplasty. J Bone Joint Surg Br 2007;89:434–40.
331
[7] Healy WL, Lo TC, DeSimone AA, Rask B, Pfeifer BA. Single-dose irradiation for the prevention of heterotopic ossification after total hip arthroplasty. A comparison of doses of five hundred and fifty and seven hundred centigray. J Bone Joint Surg Am 1995;77:590–5. [8] Fijn R, Koorevaar RT, Brouwers JR. Prevention of heterotopic ossification after total hip replacement with NSAIDs. Pharm World Sci 2003;25:138–45. [9] Ahrengart L. Periarticular heterotopic ossification after total hip arthroplasty risk factors and consequences. Clin Orthop Relat Res 1991:49–58. [10] Mormann M, Thederan M, Nackchbandi I, et al. Lipopolysaccharides (LPS) induce the differentiation of human monocytes to osteoclasts in a tumour necrosis factor (TNF) alpha-dependent manner: a link between infection and pathological bone resorption. Mol Immunol 2008;45:3330–7. [11] Cho DR, Shanbhag AS, Hong CY, Baran GR, Goldring SR. The role of adsorbed endotoxin in particle-induced stimulation of cytokine release. J Orthop Res 2002;20:704–13. [12] Greenfield EM, Bi Y, Ragab AA, et al. Does endotoxin contribute to aseptic loosening of orthopedic implants? J Biomed Mater Res B Appl Biomater 2005;72:179–85. [13] Orcel P, Feuga M, Bielakoff J, De Vernejoul MC. Local bone injections of LPS and M-CSF increase bone resorption by different pathways in vivo in rats. Am J Physiol 1993;264:E391–7. [14] Peek FA, Huisman MA, Berckmans RJ, et al. Lipopolysaccharide concentration and bone resorption in cholesteatoma. Otol Neurotol 2003;24:709–13. [15] Islam S, Hassan F, Tumurkhuu G, et al. Bacterial lipopolysaccharide induces osteoclast formation in RAW 264.7 macrophage cells. Biochem Biophys Res Commun 2007;360:346–51. [16] Dumitrescu AL, Abd-El-Aleem S, Morales-Aza B, Donaldson LF. A model of periodontitis in the rat: effect of lipopolysaccharide on bone resorption, osteoclast activity, and local peptidergic innervation. J Clin Periodontol 2004;31:596–603. [17] Shuto T, Jimi E, Kukita T, Hirata M, Koga T. Granulocyte-macrophage colony stimulating factor suppresses lipopolysaccharide-induced osteoclastlike cell formation in mouse bone marrow cultures. Endocrinology 1994;134:831–7. [18] Abu-Amer Y, Ross FP, Edwards J, Teitelbaum SL. Lipopolysaccharidestimulated osteoclastogenesis is mediated by tumor necrosis factor via its P55 receptor. J Clin Invest 1997;100:1557–65. [19] Takami M, Kim N, Rho J, Choi Y. Stimulation by toll-like receptors inhibits osteoclast differentiation. J Immunol 2002;169:1516–23. [20] Miyazaki T, Katagiri H, Kanegae Y, et al. Reciprocal role of ERK and NF-kappaB pathways in survival and activation of osteoclasts. J Cell Biol 2000;148:333–42. [21] Itoh K, Udagawa N, Katagiri T, et al. Bone morphogenetic protein 2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-kappaB ligand. Endocrinology 2001;142:3656–62. [22] Thammasitboon K, Goldring SR, Boch JA. Role of macrophages in LPS-induced osteoblast and PDL cell apoptosis. Bone 2006;38:845–52. [23] Zhang L, Schwendeman SP. Injectable biodegradable polymer depots for minimally invasive delivery of peptides and proteins. Adv Exp Med Biol 2009;611:611–3. [24] Taguchi T, Xu L, Kobayashi H, et al. Encapsulation of chondrocytes in injectable alkali-treated collagen gels prepared using poly(ethylene glycol)-based 4armed star polymer. Biomaterials 2005;26:1247–52. [25] Fujita M, Ishihara M, Simizu M, et al. Vascularization in vivo caused by the controlled release of fibroblast growth factor-2 from an injectable chitosan/ non-anticoagulant heparin hydrogel. Biomaterials 2004;25:699–706.