Dataset Information

The HGF/Met/NF-?B Pathway Regulates RANKL Expression in Osteoblasts and Bone Marrow Stromal Cells.

ABSTRACT: Multiple myeloma (MM)-induced bone disease occurs through hyperactivation of osteoclasts by several factors secreted by MM cells. MM cell-secreted factors induce osteoclast differentiation and activation via direct and indirect actions including enhanced expression of receptor activator of nuclear factor ?B ligand (RANKL) in osteoblasts and bone marrow stromal cells (BMSCs). Hepatocyte growth factor (HGF) is elevated in MM patients and is associated with MM-induced bone disease, although the mechanism by which HGF promotes bone disease remains unclear. In the present study, we demonstrated that HGF induces RANKL expression in osteoblasts and BMSCs, and investigated the mechanism of induction. We found that HGF and MM cell supernatants induced RANKL expression in ST2 cells, MC3T3-E1 cells, and mouse BMSCs. In addition, HGF increased phosphorylation of Met and nuclear factor ?B (NF-?B) in ST2 cells, MC3T3-E1 cells, or mouse BMSCs. Moreover, Met and NF-?B inhibitors suppressed HGF-induced RANKL expression in ST2 cells, MC3T3-E1 cells, and mouse BMSCs. These results indicated that HGF promotes RANKL expression in osteoblasts and BMSCs via the Met/NF-?B signaling pathway, and Met and NF-?B inhibitors suppressed HGF-induced RANKL expression. Our findings suggest that Met and NF-?B inhibitors are potentially useful in mitigating MM-induced bone disease in patients expressing high levels of HGF.

SUBMITTER: Tsubaki M

PROVIDER: S-EPMC7663721 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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The HGF/Met/NF-κB Pathway Regulates RANKL Expression in Osteoblasts and Bone Marrow Stromal Cells.

Tsubaki Masanobu M Seki Shiori S Takeda Tomoya T Chihara Akiko A Arai Yuuko Y Morii Yuusuke Y Imano Motohiro M Satou Takao T Shimomura Kazunori K Nishida Shozo S

International journal of molecular sciences 20201024 21

Multiple myeloma (MM)-induced bone disease occurs through hyperactivation of osteoclasts by several factors secreted by MM cells. MM cell-secreted factors induce osteoclast differentiation and activation via direct and indirect actions including enhanced expression of receptor activator of nuclear factor κB ligand (RANKL) in osteoblasts and bone marrow stromal cells (BMSCs). Hepatocyte growth factor (HGF) is elevated in MM patients and is associated with MM-induced bone disease, although the mec ...[more]

PMID: 33114380

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Project description:Bone marrow stromal cells (BMSCs) produce long-lasting attenuation of pain hypersensitivity. This effect involves BMSC's ability to interact with the immune system and activation of the endogenous opioid receptors in the pain modulatory circuitry. The nuclear factor kappa B (NF-?B) protein complex is a key transcription factor that regulates gene expression involved in immunity. We tested the hypothesis that the NF-?B signaling plays a role in BMSC-induced pain relief. We focused on the rostral ventromedial medulla (RVM), a key structure in the descending pain modulatory pathway, that has been shown to play an important role in BMSC-produced antihyperalgesia. In Sprague-Dawley rats with a ligation injury of the masseter muscle tendon (TL), BMSCs (1.5 M/rat) from donor rats were infused i.v. at 1 week post-TL. P65 exhibited predominant neuronal localization in the RVM with scattered distribution in glial cells. At 1 week, but not 8 weeks after BMSC infusion, western blot and immunostaining showed that p65 of NF-?B was significantly increased in the RVM. Given that chemokine signaling is critical to BMSCs' pain-relieving effect, we further evaluated a role of chemokine signaling in p65 upregulation. Prior to infusion of BMSCs, we transduced BMSCs with Ccl4 shRNA, incubated BMSCs with RS 102895, a CCR2b antagonist, or maraviroc, a CCR5 antagonist. The antagonism of chemokines significantly reduced BMSC-induced upregulation of p65, suggesting that upregulation of p65 was related to BMSCs' pain-relieving effect. We then tested the effect of a selective NF-?B activation inhibitor, BAY 11-7082. The mechanical hyperalgesia of the rat was assessed with the von Frey method. In the pre-treatment experiment, BAY 11-7082 (2.5 and 25 pmol) was injected into the RVM at 2 h prior to BMSC infusion. Pretreatment with BAY 11-7082 attenuated BMSCs' antihyperalgesia, but post-treatment at 5 weeks post-BMSC was not effective. On the contrary, in TL rats receiving BAY 11-7082 without BMSCs, TL-induced hyperalgesia was attenuated, consistent with dual roles of NF-?B in pain hypersensitivity and BMSC-produced pain relief. These results indicate that the NF-?B signaling pathway in the descending circuitry is involved in initiation of BMSC-produced behavioral antihyperalgesia.

Dataset Information

The HGF/Met/NF-?B Pathway Regulates RANKL Expression in Osteoblasts and Bone Marrow Stromal Cells.

Publications

The HGF/Met/NF-κB Pathway Regulates RANKL Expression in Osteoblasts and Bone Marrow Stromal Cells.

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