BMSC paracrine activity attenuates interleukin-1β-induced inflammation and apoptosis in rat AF cells via inhibiting relative NF-κB signaling and the mitochondrial pathway.
Hu Jinquan,Yan Qiang,Shi Changgui,Tian Ye,Cao Peng,Yuan Wen
American journal of translational research
We previously showed that bone mesenchymal stem cells (BMSCs) inhibit interleukin-1 beta (IL-1β) induced degenerative effects in NP cells by their paracrine activity, but the anti-inflammatory and anti-apoptotic effect of BMSC paracrine activity and the relative signaling pathway were not further investigated in annulus fibrosus (AF) cells. In this study, AF cells were exposed to IL-1β, which was applied to mimic intervertebral disc degeneration (IDD) . Indirect co-culture with BMSCs in a transwell co-culture system reduced the activity of nuclear factor-κB-p65 (NF-κB-p65) through the restoration of its inhibitor IκBa. Real time polymerase chain reaction (PT-PCR) and Western blotting revealed that the up-regulation of MMP-3 and MMP-13 induced by IL-1β were impeded by BMSC co-culture, and the decrease in aggrecan, collagen I and TIMP-1 were reversed. An ELISA showed that the increased inflammatory factors, such as nitrite, prostaglandin E-2 (PGE-2), IL-6 and cyclooxygenase-2 (COX-2), were decreased by the BMSC co-culture. Furthermore, the apoptosis rate of AF cells were detected by flow cytometry, and the apoptosis-related proteins, such as Bax, Bcl-2 and caspase-3, were analyzed by Western blotting and ELISA. The changes in mitochondrial membrane potentials were also detected by confocal microscopy. The results showed that IL-1β induced apoptosis of AF cells was attenuated by co-culturing, which suppressed the functions of the mitochondria function. We suggest that BMSC paracrine activity has an anti-inflammation effect and anti-apoptotic effect on IDD, and it is mediated, at least in part, via the relative NF-κF and mitochondrial apoptotic pathways in AF cells.
Identification of osteoclast-osteoblast coupling factors in humans reveals links between bone and energy metabolism.
Weivoda Megan M,Chew Chee Kian,Monroe David G,Farr Joshua N,Atkinson Elizabeth J,Geske Jennifer R,Eckhardt Brittany,Thicke Brianne,Ruan Ming,Tweed Amanda J,McCready Louise K,Rizza Robert A,Matveyenko Aleksey,Kassem Moustapha,Andersen Thomas Levin,Vella Adrian,Drake Matthew T,Clarke Bart L,Oursler Merry Jo,Khosla Sundeep
Bone remodeling consists of resorption by osteoclasts followed by formation by osteoblasts, and osteoclasts are a source of bone formation-stimulating factors. Here we utilize osteoclast ablation by denosumab (DMAb) and RNA-sequencing of bone biopsies from postmenopausal women to identify osteoclast-secreted factors suppressed by DMAb. Based on these analyses, LIF, CREG2, CST3, CCBE1, and DPP4 are likely osteoclast-derived coupling factors in humans. Given the role of Dipeptidyl Peptidase-4 (DPP4) in glucose homeostasis, we further demonstrate that DMAb-treated participants have a significant reduction in circulating DPP4 and increase in Glucagon-like peptide (GLP)-1 levels as compared to the placebo-treated group, and also that type 2 diabetic patients treated with DMAb show significant reductions in HbA1c as compared to patients treated either with bisphosphonates or calcium and vitamin D. Thus, our results identify several coupling factors in humans and uncover osteoclast-derived DPP4 as a potential link between bone remodeling and energy metabolism.