Bisphosphonate Modulates Cementoblast Behavior In Vitro

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142297/1/jper1890.pd

Regulation of Cementoblast Gene Expression by Inorganic Phosphate In Vitro

Examination of mutant and knockout phenotypes with altered phosphate/pyrophosphate distribution has demonstrated that cementum, the mineralized tissue that sheathes the tooth root, is very sensitive to local levels of phosphate and pyrophosphate. The aim of this study was to examine the potential regulation of cementoblast cell behavior by inorganic phosphate (P i ). Immortalized murine cementoblasts were treated with P i in vitro , and effects on gene expression (by quantitative real-time reverse-transcriptase polymerase chain reaction [RT-PCR]) and cell proliferation (by hemacytometer count) were observed. Dose-response (0.1–10 mM) and time-course (1–48 hours) assays were performed, as well as studies including the Na-P i uptake inhibitor phosphonoformic acid. Real-time RT-PCR indicated regulation by phosphate of several genes associated with differentiation/mineralization. A dose of 5 mM P i upregulated genes including the SIBLING family genes osteopontin ( Opn , >300% of control) and dentin matrix protein-1 ( Dmp-1 , >3,000% of control). Another SIBLING family member, bone sialoprotein ( Bsp ), was downregulated, as were osteocalcin ( Ocn ) and type I collagen ( Col1 ). Time-course experiments indicated that these genes responded within 6–24 hours. Time-course experiments also indicated rapid regulation (by 6 hours) of genes concerned with phosphate/pyrophosphate homeostasis, including the mouse progressive ankylosis gene ( Ank ), plasma cell membrane glycoprotein-1 ( Pc-1 ), tissue nonspecific alkaline phosphatase ( Tnap ), and the Pit1 Na-P i cotransporter. Phosphate effects on cementoblasts were further shown to be uptake-dependent and proliferation-independent. These data suggest regulation by phosphate of multiple genes in cementoblasts in vitro . During formation, phosphate and pyrophosphate may be important regulators of cementoblast functions including maturation and regulation of matrix mineralization.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/48015/1/223_2005_Article_184.pd

Zoledronic acid up-regulates bone sialoprotein expression in osteoblastic cells through Rho GTPase inhibition

Clinical practice reveals that osteoporotic women treated with BPs (bisphosphonates) show an increased bone mass density and a reduced risk of fractures. However, the mechanisms leading to these beneficial effects of BPs are still poorly understood. We hypothesized that ZOL (zoledronic acid), a potent third-generation BP, may induce the expression of proteins associated with the bone-forming potential of osteoblastic cells such as BSP (bone sialoprotein). Expression of BSP gene is up-regulated by hormones that promote bone formation and has been associated with de novo bone mineralization. Using real-time reverse transcriptase-PCR and Western-blot analysis, we demonstrated that ZOL increased BSP expression in Saos-2 osteoblast-like cells. Nuclear run-on and mRNA decay assays showed no effect at the transcriptional level but a stabilization of BSP transcripts in ZOL-treated cells. ZOL effect on BSP expression occurred through an interference with the mevalonate pathway since it was reversed by either mevalonate pathway intermediates or a Rho GTPase activator. We showed that ZOL impaired membrane localization of RhoA in Saos-2 cells indicating reduced prenylation of this protein. By the use of small interfering RNAs directed to RhoA and Rac1, we identified both Rho GTPases as negative regulators of BSP expression in Saos-2 cells. Our study demonstrates that ZOL induces BSP expression in osteoblast-like cells through inactivation of Rho GTPases and provides a potential mechanism to explain the favourable effects of ZOL treatment on bone mass and integrity

What impact do systemically administrated bisphosphonates have on oral implant therapy? A systematic review.

OBJECTIVES: The aim of this systematic review is to evaluate, analysing the dental literature, whether: * Patients on intravenous (IV) or oral bisphosphonates (BPs) can receive oral implant therapy and what could be the risk of developing bisphosphonate-related osteonecrosis of the jaw (BRONJ)? * Osseointegrated implants could be affected by BP therapy. MATERIAL AND METHODS: A Medline search was conducted and all publications fulfilling the inclusion and exclusion criteria from 1966 until December 2008 were included in the review. Moreover, the Cochrane Data Base of Systematic Reviews, and the Cochrane Central Register of Controlled Trials and EMBASE (from 1980 to December 2008) were searched for English-language articles published between 1966 and 2008. Literature search was completed by a hand research accessing the references cited in all identified publications. RESULTS: The literature search rendered only one prospective and three retrospective studies. The prospective controlled non-randomized clinical study followed patients with and without BP medication up to 36 months after implant therapy. The patients in the experimental group had been on oral BPs before implant therapy for periods ranging between 1 and 4 years. None of the patients developed BRONJ and implant outcome was not affected by the BP medication. The three selected retrospective studies (two case-controls and one case series) yielded very similar results. All have followed patients on oral BPs after implant therapy, with follow-up ranging between 2 and 4 years. BRONJ was never reported and implant survival rates ranged between 95% and 100%. The literature search on BRONJ including guidelines and recommendations found 59 papers, from which six were retrieved. Among the guidelines, there is a consensus on contraindicating implants in cancer patients under IV-BPs and not contraindicating dental implants in patients under oral-BPs for osteoporosis. CONCLUSIONS: From the analysis of the one prospective and the three retrospective series (217 patients), the placement of an implant may be considered a safe procedure in patients taking oral BPs for <5 years with regard to the occurrence of BRONJ since in these studies no BRONJ has been reported. Moreover, the intake of oral-BPs did not influence short-term (1-4 years) implant survival rates