Bisphosphonate modulates proliferation and differentiation of rat periodontal ligament cells during wound healing

Lekic, P.; Rubbino, I.; Krasnoshtein, Flora; Cheifetz, Sela; McCulloch, Christopher A.; Tenenbaum, Henri

doi:10.1002/(sici)1097-0185(199703)247:3<329::aid-ar4>3.0.co;2-p

Cited by 41 publications

(64 citation statements)

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“…However, despite expression of BSP in all the soft tissues, no ectopic calcification was detected in the adult transgenic mice. Although some studies associated BSP with ectopic calcification, (25)(26)(27) recent reports have suggested that expression of BSP may not be sufficient to promote ectopic calcification. (50,51) These recent reports, together with our results that CMV-BSP mice lacks ectopic calcification, suggest that increasing the BSP level alone is not sufficient to induce ectopic calcification in the tissues that do not express BSP under physiological conditions (i.e., liver, kidney, periodontal ligament).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its ability to nucleate hydroxyapatite crystal formation and promote mineralization, (17,18) BSP was also reported to induce cell adhesion (19,20) and increase osteoclastogenesis and bone resorption. (21)(22)(23)(24) Furthermore, although BSP expression is coincident with de novo bone formation (14,15) and ectopic calcification, (25)(26)(27) high BSP level in serum under pathological conditions has been associated with excessive bone resorption. For example, BSP expression was detected in many malignant tumor cells with a tendency of metastasis to bone and high serum BSP level was reported in patients suffering from osteotropic cancers and tumor-associated bone loss.…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of Bone Sialoprotein Leads to an Uncoupling of Bone Formation and Bone Resorption in Mice

Valverde

Zhang

Fix

et al. 2008

Journal of Bone and Mineral Research

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ABSTRACT:The purpose of this study was to determine the effects of bone sialoprotein (BSP) overexpression in bone metabolism in vivo by using a homozygous transgenic mouse line that constitutively overexpresses mouse BSP cDNA driven by the cytomegalovirus (CMV) promoter. CMV-BSP transgenic (TG) mice and wildtype mice were weighed, and their length, BMD, and trabecular bone volume were measured. Serum levels of RANKL, osteocalcin, osteoprotegerin (OPG), TRACP5b, and PTH were determined. Bone histomorphometry, von Kossa staining, RT-PCR analysis, Western blot, MTS assay, in vitro mineralization assay, and TRACP staining were also performed to delineate phenotypes of this transgenic mouse line. Compared with wildtype mice, adult TG mice exhibit mild dwarfism, lower values of BMD, and lower trabecular bone volume. TG mice serum contained increased calcium levels and decreased PTH levels, whereas the levels of phosphorus and magnesium were within normal limits. TG mice serum also exhibited lower levels of osteoblast differentiation markers and higher levels of markers, indicating osteoclastic activity and bone resorption. H&E staining, TRACP staining, and bone histomorphometry showed that adult TG bones were thinner and the number of giant osteoclasts in TG mice was higher, whereas there were no significant alterations in osteoblast numbers between TG mice and WT mice. Furthermore, the vertical length of the hypertrophic zone in TG mice was slightly enlarged. Moreover, ex vivo experiments indicated that overexpression of BSP decreased osteoblast population and increased osteoclastic activity. Partly because of its effects in enhancing osteoclastic activity and decreasing osteoblast population, BSP overexpression leads to an uncoupling of bone formation and resorption, which in turn results in osteopenia and mild dwarfism in mice. These findings are expected to help the development of therapies to metabolic bone diseases characterized by high serum level of BSP.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Overexpression of Bone Sialoprotein Leads to an Uncoupling of Bone Formation and Bone Resorption in Mice

Valverde

Zhang

Fix

et al. 2008

Journal of Bone and Mineral Research

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“…The rationale for using the two systems was that with both, detailed assessment of a much wider variety of outcome measures could be performed than if only one system were used. Moreover, although many findings produced in the CPO model have been replicated in mammalian systems in vitro and in vivo (Tenenbaum 1981, McCulloch & Tenenbaum 1986, Kamalia et al 1992, Lekic et al 1997, Sukhu et al 1997, it was still thought appropriate to utilize a mammalian model system like the SBMC model. Finally, it was thought that if the data produced in both systems were parallel to one another, the validity of those findings would be strengthened and this would reduce the likelihood that the data were related to species or a culture system artifact.…”

Section: Rationale For Use Of Proposed In Vitro Modelsmentioning

confidence: 99%

Inhibition of dioxin effects on bone formation in vitro by a newly described aryl hydrocarbon receptor antagonist, resveratrol

Singh¹,

Casper²,

Fritz³

et al. 2000

Journal of Endocrinology

131

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Aryl hydrocarbon receptor (AhR) ligands are environmental contaminants found in cigarette smoke and other sources of air pollution. The prototypical compound is TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), also known as dioxin. There is an increasing body of knowledge linking cigarette smoking to osteoporosis and periodontal disease, but the direct effects of smokeassociated aryl hydrocarbons on bone are not well understood. Through the use of resveratrol (3,5,4 -trihydroxystilbene), a plant antifungal compound that we have recently demonstrated to be a pure AhR antagonist, we have investigated the effects of TCDD on osteogenesis. It was postulated that TCDD would inhibit osteogenesis in bone-forming cultures and that this inhibition would be antagonized by resveratrol. We employed the chicken periosteal osteogenesis (CPO) model, which has been shown to form bone in vitro in a pattern morphologically and biochemically similar to that seen in vivo, as well as a rat stromal cell bone nodule formation model. In the CPO model, alkaline phosphatase (AP) activity was reduced by up to 50% (P<0·01 vs control) in the presence of 10 9 M TCDD and these effects were reversed by 10 6 M resveratrol (P<0·05 vs TCDD alone). TCDD-mediated inhibition of osteogenesis was restricted primarily to the osteoblastic differentiation phase (days 0-2) as later addition did not appear to have any effects. Message levels for important bone-associated proteins (in the CPO model) such as collagen type I, osteopontin, bone sialoprotein and AP were inhibited by TCDD, an effect that was antagonized by resveratrol. Similar findings were obtained using the rat stromal bone cell line. TCDD (at concentrations as low as 10 10 M) caused an approximately 33% reduction in AP activity, which was abrogated by 3·5 10 7 M resveratrol. TCDD also induced a marked reduction in mineralization (75%) which was completely antagonized by resveratrol. These data suggest that AhR ligands inhibit osteogenesis probably through inhibition of osteodifferentiation and that this effect can be antagonized by resveratrol. Since high levels of AhR ligands are found in cigarette smoke, and further since smoking is an important risk factor in both osteoporosis and periodontal disease, it may be postulated that AhR ligands are the component of cigarette smoke linking smoking to osteoporosis and periodontal disease. If so, resveratrol could prove to be a promising preventive or therapeutic agent for smoking-related bone loss.

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“…The animal protocol was approved by the Institutional Animal Use and Care Committee at the Tufts-New England Medical Center in Boston (Massachusetts). 19,20 In brief, a skin flap was raised along the lower edge of the mandible to expose the underlying bone. The site of the window wound was 1 mm away from the anterior edge of the mandible and between the superior margin of the alveolar bone overlying the mesial root of the lower first molar and the foramen mentale.…”

Section: Animalsmentioning

confidence: 99%

Cbfa1/Runx2‐deficiency delays bone wound healing and locally delivered Cbfa1/Runx2 promotes bone repair in animal models

Zhang

James

et al. 2007

Wound Repair Regeneration

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Core binding factor 1 (Cbfa1)/runt-related transcription factor 2 (Runx2) has been identified as a ''master gene'' in osteoblastic differentiation. In this two-part study, part I of the study was undertaken to test the hypothesis that bone regeneration is compromised in Cbfa1+/− mice. Compared with wild-type mice, wound healing was dramatically delayed in Cbfa1+/− mice characterized by the presence of a small amount of bone near the base of the wounds. The bone defects were largely filled with fibrous connective tissues 3 weeks after surgery. Part II was performed to determine the effects of Cbfa1 in enhancing bone wound healing using a gene-activated matrix (GAM) method. Cbfa1 cDNA was mixed with a biodegradable bovine type I collagen sponge and was inserted into the periodontal window wounds of mice. Control sponges were collagen matrix without Cbfa1 cDNA. Histological analysis and immunohistochemical staining demonstrated that compared with controls, there was increased new bone formation that almost filled the wound defects 14 days after surgery in the Cbfa1-GAM group. The collagen sponge matrix did not seem to elicit significant foreign body reaction in either group. In conclusion, the reduced expression of Cbfa1 interferes with the process of bone wound healing, and local application of Cbfa1 cDNA incorporated into a collagen matrix promotes bone tissue regeneration.Millions of Americans are afflicted with periodontal diseases that cause destruction of supporting structures of teeth: periodontal ligament (PDL), alveolar bone, and cementum. The process can lead to the loss of attachment, with destruction of the connective tissue matrix and cells. Loosening and eventual loss of teeth may follow. However, despite considerable research efforts in this area, regeneration of the periodontium has still proved to be an elusive goal of periodontal therapy and remains a subject of intense interest to dentists and dental scientists, with the molecular and cellular bases of PDL formation, repair, and regeneration still poorly understood.In the 1980s, Gould observed that the progenitor cells for cementum, bone, and PDL fibroblasts were all contained in PDL tissue. 1 He described generation of a new, functionally oriented PDL when teeth bearing cultured PDL cells were transplanted into bony sites. By contrast, the transplantation of teeth bearing cultured gingival cells did not lead to regeneration of the PDL. These early studies indicated that regeneration of damaged periodontium can be achieved by Similar to adipocyte 3 and myoblast 4 differentiation, it is apparent that components of the extracellular matrix are also critical for initiating cell differentiation during osteogenesis. 5 In the 1990s, independent studies of a transcription factor that regulated the tissue-specific expression of osteocalcin (OCN) 6,7 and analysis of transgenic knockouts 8,9 resulted in the identification of core-binding factor 1 (Cbfa1), a runt domain transcription factor and its cognate enhancer. This transcription factor, also r...

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Bisphosphonate modulates proliferation and differentiation of rat periodontal ligament cells during wound healing

Cited by 41 publications

References 40 publications

Overexpression of Bone Sialoprotein Leads to an Uncoupling of Bone Formation and Bone Resorption in Mice

Overexpression of Bone Sialoprotein Leads to an Uncoupling of Bone Formation and Bone Resorption in Mice

Inhibition of dioxin effects on bone formation in vitro by a newly described aryl hydrocarbon receptor antagonist, resveratrol

Cbfa1/Runx2‐deficiency delays bone wound healing and locally delivered Cbfa1/Runx2 promotes bone repair in animal models

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