Abstract
Bone loss due to an increased osteoclast activity is common in osteoporosis and rheumatoid arthritis. For the first time, we observed an inhibition of osteoclast formation and bone resorption by outer-membrane vesicles (OMVs) from a Gram-negative, pathogenic bacterium, Proteus mirabilis (P.M). Gene ontogeny and KEGG enrichment analyses of miRNA and mRNA sequencing data demonstrated a significant effect of P.M OMVs on mitochondrial functions and apoptotic pathways. OMVs induced mitochondrial dysfunction through an increased level of intracellular ROS, collapse of mitochondrial membrane potential (ΔΨm), and modulation of Bax, Bcl-2, caspase-3, and cytochrome c expression. In addition, P.M OMVs strongly inhibited miR-96-5p expression, which caused an upregulation of ATP binding cassette subfamily A member 1 (Abca1) in osteoclasts leading to an increased level of mitochondria-dependent apoptosis. Moreover, treatment with P.M but not Escherichia coli OMVs attenuated bone loss in experimental osteoporosis and collagen-induced arthritis. Collectively, we demonstrated osteoprotective functions of OMVs from Proteus mirabilis, which downregulated miR-96-5p causing an increased Abca1 expression and mitochondria-dependent apoptosis.
Highlights
Bone loss is a characteristic feature of several diseases like osteoporosis (OP), rheumatoid arthritis (RA) [1], lupus [2], Alzheimer’s disease [3], and in certain cancers [4]
Based on the information from a microbe–disease interaction database (MDIDB), four bacteria related to RA and osteoporosis (E. coli, P. mirabilis, L. casei, and L. acidophilus) were chosen (Figure S1A)
We have analyzed the effects of outer-membrane vesicles (OMVs) from a pathogenic bacterium Proteus mirabilis on osteoclasts at three levels and demonstrated how a pathogenic bacterium could protect against bone loss
Summary
Bone loss is a characteristic feature of several diseases like osteoporosis (OP), rheumatoid arthritis (RA) [1], lupus [2], Alzheimer’s disease [3], and in certain cancers [4]. An increase in osteoclast numbers and function causes bone disorders [5]. Fusion and terminal differentiation of mononuclear precursor cells lead to osteoclast formation, which has the unique ability to resorb bone matrix by secreting various matrix lysing enzymes [6]. A balance between cell differentiation and death determines the number of osteoclasts. Bone resorption could be improved by reducing the formation of osteoclasts and increasing their death rate. Apoptosis plays an important regulatory role in the osteoclast-mediated bone resorption in which a Bacterial Vesicles Inhibit Osteoclast Differentiation critical role for mitochondria-dependent pathways is observed [7]. An increased level of OC apoptosis in transgenic mice led to reduced bone resorption and osteopetrosis [9]. Targeting osteoclastogenesis and osteoclast apoptosis could improve bone loss
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