Nitrogen Containing Bisphosphonates Impair the Release of Bone Homeostasis Mediators and Matrix Production by Human Primary Pre-Osteoblasts

Giannasi, Chiara; Niada, Stefania; Farronato, Davide; Lombardi, Giovanni; Manfredi, Barbara; Farronato, Giampietro; Brini, A.T.

doi:10.7150/ijms.27470

Cited by 15 publications

(11 citation statements)

References 44 publications

(39 reference statements)

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“…In details, OPG and DKK-1 were quantified with the Human Bone Magnetic Bead Panel-Bone Metabolism Multiplex Assay (HBNMAG-51K, Millipore, Burlington, MA, USA), MMP1 and 2 with the Human MMP Magnetic Bead Panel 2 (HMMP2MAG-55 K, Millipore, Burlington, MA, USA), while TIMP-1,- 2 and -3 with the Human TIMP Magnetic Luminex Performance Assay (LKTM003, R&D Systems, Minneapolis, MN, USA). Technical duplicates were analyzed for each CM sample following previously described procedures [ 27 , 47 ] and data analysis was performed with the MAGPIX xPONENT 4.2 software (Luminex Corporation, Austin, TX, USA). The concentration of the selected molecules is reported in Supplementary Table 3 along with the processes in which each factor is involved, as indicated in Supplementary Table 2 .…”

Section: Methodsmentioning

confidence: 99%

Comparison of two ASC-derived therapeutics in an in vitro OA model: secretome versus extracellular vesicles

et al. 2020

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Background In the last years, several clinical trials have proved the safety and efficacy of adipose-derived stem/stromal cells (ASC) in contrasting osteoarthritis (OA). Since ASC act mainly through paracrine mechanisms, their secretome (conditioned medium, CM) represents a promising therapeutic alternative. ASC-CM is a complex cocktail of proteins, nucleic acids, and lipids released as soluble factors and/or conveyed into extracellular vesicles (EV). Here, we investigate its therapeutic potential in an in vitro model of OA. Methods Human articular chondrocytes (CH) were induced towards an OA phenotype by 10 ng/ml TNFα in the presence of either ASC-CM or EV, both deriving from 5 × 105 cells, to evaluate the effect on hypertrophic, catabolic, and inflammatory markers. Results Given the same number of donor cells, our data reveal a higher therapeutic potential of ASC-CM compared to EV alone that was confirmed by its enrichment in chondroprotective factors among which TIMP-1 and -2 stand out. In details, only ASC-CM significantly decreased MMP activity (22% and 29% after 3 and 6 days) and PGE2 expression (up to 40% at day 6) boosted by the inflammatory cytokine. Conversely, both treatments down-modulated of ~ 30% the hypertrophic marker COL10A1. Conclusions These biological and molecular evidences of ASC-CM beneficial action on CH with an induced OA phenotype may lay the basis for its future clinical translation as a cell-free therapeutic in the management of OA.

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Section: Methodsmentioning

confidence: 99%

Comparison of two ASC-derived therapeutics in an in vitro OA model: secretome versus extracellular vesicles

et al. 2020

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“…In the last decade, some authors provided us with interesting data about the action of ZOL on proliferation capability and survival of human pre-osteoblast, oral fibroblast, and epithelial cells, as well as osteoclast and bone marrow stem cells-derived osteoblast 33 – 35 . Nevertheless, the action of ZOL on PDLSCs has been poorly investigated.…”

Section: Discussionmentioning

confidence: 99%

Dose-Dependent Effects of Zoledronic Acid on Human Periodontal Ligament Stem Cells: An In Vitro Pilot Study

et al. 2020

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Bisphosphonates (BPs) are widely used to treat several metabolic and oncological diseases affecting the skeletal system. Despite BPs’ well-known therapeutic potential, they also displayed important side effects, among which is BPs-related osteonecrosis of the jaw, by targeting osteoclast activities, osteoblast, and osteocyte behavior. The aim of this study is to evaluate the biological effects of zoledronic acid (ZOL) in an in vitro model of periodontal ligament stem cells (PDLSCs) by using an experimental setting that resembles the in vivo conditions. PDLSCs were treated with different concentrations of ZOL ranging from 0.1 to 5 μM. The effects of ZOL exposure were evaluated on cell viability via 3-[4,5-Dimethylthiaoly]-2,5-diphenyltetrazolium bromide (MTT), cell cycle analysis, apoptosis detection, and immunofluorescence. Quantitative real-time polymerase chain reaction (PCR), colorimetric detection of alkaline phosphatase activity, and Alizarin Red S staining were performed to investigate the osteogenic potential of PDLSCs exposed to ZOL. MTT analysis showed that the viability of PDLSCs exposed to ZOL concentration ≥1.5 μM for 3 and 6 days was significantly lower ( P < 0.001) than that of untreated cells. The percentage of apoptotic cells was significantly higher in PDLSCs exposed for 4 days to ZOL at 2 μM ( P < 0.01) and 5 μM ( P < 0.001) when compared to the control. Moreover, ZOL treatment (3 days) accounted for alterations in cell cycle distribution, with an increase in the proportion of cells in G0/G1 phase and a reduction in the proportion of cells in S phase. Chronic exposure (longer than 7 days) of PDLSCs to ZOL accounted for the downregulation of ALP, RUNX2, and COL1 genes at all tested concentrations, which fit well with the reduced alkaline phosphatase activity reported after 7 and 14 days of treatment. Reduced Col1 deposition in the extracellular matrix was reported after 14 days of treatment. Increased calcium deposits were observed in treated cells when compared to the control cultures. In conclusion, chronic exposure to 1 μM ZOL induced significant reduction of osteogenic differentiation, while ZOL concentrations ≥1.5 μM are required to impair PDLSCs viability and induce apoptosis.

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“…The conflicting apoptotic and antiapoptotic effects could be explained by the different bisphosphonates studied and concentrations used [ 41 ]. Mounting evidence suggests that cells of the osteoblast lineage are affected directly by bisphosphonates in a dose-dependent manner that contributes to the development of BONJ [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Altered Long Noncoding RNA Expression Profile in Multiple Myeloma Patients with Bisphosphonate-Induced Osteonecrosis of the Jaw

Allegra

Mania

D’Ascola

et al. 2020

BioMed Research International

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Bisphosphonates (BPs) are inhibitors of osteoclast-mediated bone resorption used for the treatment of multiple myeloma (MM) patients with osteolytic lesions. Bisphosphonate-induced osteonecrosis of the jaw (BONJ) is an infrequent drug-caused adverse event of these agents. Long noncoding RNAs (lncRNAs) are a set of more than 200 base pairs, noncoding RNA molecules, which are critical posttranscriptional regulators of gene expression. Our study was aimed at evaluating 17 lncRNAs, whose targets were previously validated as key elements in MM, bone metabolism, and angiogenesis in MM subjects without BONJ (MM group), in MM subjects with BONJ (BONJ group), and a group of healthy controls (CTRL group). Our results demonstrated a different lncRNA profile in BONJ patients compared to MM patients and controls. Two lncRNAs (DANCR and MALAT1) were both downregulated compared to controls and MM, twelve (HOTAIR, MEG3, TP73-AS1, HOTTIP, HIF1A-AS2, MANTIS, CTD-2201E18, CTD1-2003C8, R-471B22, RP1-43E13, RP11-553L6.5, and RP1-286D6) were overexpressed in MM with BONJ, and one (H19) was upregulated compared with only MM. Two lncRNAs (JHDMD1 and MTMR9LP) had higher expression, but these differences were not statistically significant. The examined lncRNAs target several genes and metabolic pathways. An altered lncRNA signature could contribute to the onset of BONJ or have a protective action. Targeting these lncRNAs could offer a possibility for the prevention or therapy of BONJ.

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Nitrogen Containing Bisphosphonates Impair the Release of Bone Homeostasis Mediators and Matrix Production by Human Primary Pre-Osteoblasts

Cited by 15 publications

References 44 publications

Comparison of two ASC-derived therapeutics in an in vitro OA model: secretome versus extracellular vesicles

Comparison of two ASC-derived therapeutics in an in vitro OA model: secretome versus extracellular vesicles

Dose-Dependent Effects of Zoledronic Acid on Human Periodontal Ligament Stem Cells: An In Vitro Pilot Study

Altered Long Noncoding RNA Expression Profile in Multiple Myeloma Patients with Bisphosphonate-Induced Osteonecrosis of the Jaw

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