Binding Immunoglobulin Protein (BiP) Inhibits TNFα-Induced Osteoclast Differentiation and Systemic Bone Loss in an Erosive Arthritis Model: BiP inhibits osteoclasts in an arthritis model

Mario M. Zaiss, Christopher Hall, Neil WA McGowan, Rebecca Babb, Vikesh Devlia, Sebastian Lucas, Sajeda Meghji, Brian Henderson, Aline Bozec, Georg Schett, Jean-Pierre David, Gabriel S Panayi, Agamemnon E. Grigoriadis, Valerie Corrigall

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Abstract

Objective: The association between inflammation and dysregulated bone remodelling is apparent in rheumatoid arthritis and is recapitulated in the human TNF transgenic (hTNFtg) mouse model. We investigated whether extracellular binding immunoglobulin protein (BiP) would protect the hTNFtg mouse from both inflammatory arthritis as well as extensive systemic bone loss, and whether BiP had direct anti-osteoclast properties in vitro.
Methods: hTNFtg mice received a single intraperitoneal administration of BiP at onset of arthritis. Clinical disease parameters were measured weekly. Bone analysis was performed by micro-computed tomography and histomorphometry. Mouse bone marrow macrophage and human peripheral blood monocyte precursors were used to study the direct effect of BiP on osteoclast differentiation and function in vitro. Monocyte and osteoclast signalling was analyzed by Western blotting, flow cytometry and imaging flow cytometry.
Results: BiP-treated mice showed reduced inflammation and cartilage destruction, and histomorphometric analysis revealed a decrease in osteoclast number with protection from systemic bone loss. Abrogation of osteoclast function was also observed in an ex vivo murine calvarial model. BiP inhibited differentiation of osteoclast precursors and prevented bone resorption by mature osteoclasts in vitro. BiP also induced downregulation of CD115/c-Fms and RANK receptor mRNA and protein, causing reduced phosphorylation of the MAPKs ERK1/2 and p38, with suppression of essential osteoclast transcription factors, c-Fos and NFATc1. BiP directly inhibited TNFα- or RANKL-induced NF-κB nuclear translocation in THP-1 monocytic cells and pre-osteoclasts by the canonical and non-canonical pathways.
Conclusion: BiP combines an anti-inflammatory function with anti-osteoclast activity which establishes it as a potential novel therapeutic for inflammatory disorders associated with bone loss.
Original languageEnglish
JournalACR Open Rheumatology
DOIs
Publication statusPublished - 2019

Keywords

  • RHEUMATOID ARTHRITIS
  • BiP/GRP78
  • TNF
  • inflammation
  • OSTEOCLAST

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