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In vivo study and thermodynamic investigation of two lanthanum complexes, La(dpp)3 and La(XT), for the treatment of bone resorption disorders.

ABSTRACT: Bone density diseases such as osteoporosis affect a significant number of people worldwide. Lanthanide ions are functional mimics of calcium ions, able to substitute for Ca2+ in the bone mineral component, hydroxyapatite (HAP). Bone undergoes a continuous remodelling cycle and lanthanides can affect this cycle, exerting a positive influence on bone mineral. We have been engaged in efforts to find new lanthanide containing complexes as active agents for treatment of these diseases and have identified two lead compounds, 3-hydroxy-1,2-dimethylpyridin-4(1H)-one (Hdpp) and a phosphinate-EDTA derivative, bis[[bis(carboxymethyl)amino]-methyl]phosphinate (H5XT). In this paper, we report in vivo data for the first time for the two lead compounds. The pharmacokinetics of La(dpp)3 suggest the complex is rapidly cleared from plasma. We demonstrate that La3+ accumulates in the bone following IV dose of either La(dpp)3 or La(XT) and we have investigated the influence of each chelating ligand on the incorporation of La3+ into HAP using ITC and HAP-binding studies.

SUBMITTER: Cawthray JF

PROVIDER: S-EPMC6054118 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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In vivo study and thermodynamic investigation of two lanthanum complexes, La(dpp)3 and La(XT), for the treatment of bone resorption disorders.

Cawthray J F JF Weekes D M DM Sivak O O Creagh A L AL Ibrahim F F Iafrate M M Haynes C A CA Wasan K M KM Orvig C C

Chemical science 20150803 11

Bone density diseases such as osteoporosis affect a significant number of people worldwide. Lanthanide ions are functional mimics of calcium ions, able to substitute for Ca2+ in the bone mineral component, hydroxyapatite (HAP). Bone undergoes a continuous remodelling cycle and lanthanides can affect this cycle, exerting a positive influence on bone mineral. We have been engaged in efforts to find new lanthanide containing complexes as active agents for treatment of these diseases and ...[more]

PMID: 30090262

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Project description:ObjectiveAutoantibodies are detected in most patients with rheumatoid arthritis (RA) and can be of the IgM, IgG or IgA subclass. Correlations between IgA autoantibodies and more severe disease activity have been previously reported, but the functional role of IgA autoantibodies in the pathogenesis of RA is ill understood. In this study, we explored the effect of IgA immune complexes on osteoclast mediated bone resorption.MethodsAnti-citrullinated peptide antibody (ACPA) and anti-carbamylated protein (anti-CarP) antibody levels of the IgA and IgG isotype and rheumatoid factor (RF) IgA were determined in synovial fluid (SF) of RA patients. Monocytes, neutrophils, and osteoclasts were stimulated with precipitated immune complexes from SF of RA patients or IgA- and IgG-coated beads. Activation was determined by neutrophil extracellular trap (NET) release, cytokine secretion, and bone resorption.ResultsNET formation by neutrophils was enhanced by SF immune complexes compared to immune complexes from healthy or RA serum. Monocytes stimulated with isolated SF immune complexes released IL-6 and IL-8, which correlated with the levels of ACPA IgA levels in SF. Osteoclasts cultured in the presence of supernatant of IgA-activated monocytes resorbed significantly more bone compared to osteoclasts that were cultured in supernatant of IgG-activated monocytes (p=0.0233). Osteoclasts expressed the Fc receptor for IgA (FcαRI; CD89) and Fc gamma receptors. IgA-activated osteoclasts however produced significantly increased levels of IL-6 (p<0.0001) and IL-8 (p=0.0007) compared to IgG-activated osteoclasts. Both IL-6 (p=0.03) and IL-8 (p=0.0054) significantly enhanced bone resorption by osteoclasts.ConclusionIgA autoantibodies induce release of IL-6 and IL-8 by immune cells as well as osteoclasts, which enhances bone resorption by osteoclasts. We anticipate that this will result in more severe disease activity in RA patients. Targeting IgA-FcαRI interactions therefore represents a promising novel therapeutic strategy for RA patients with IgA autoantibodies.

Dataset Information

In vivo study and thermodynamic investigation of two lanthanum complexes, La(dpp)3 and La(XT), for the treatment of bone resorption disorders.

Publications

<i>In vivo</i> study and thermodynamic investigation of two lanthanum complexes, La(dpp)<sub>3</sub> and La(XT), for the treatment of bone resorption disorders.

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