Patients with chronic inflammatory disorders, such as rheumatoid arthritis (RA), often suffer from severe osteoporosis and increased risk of fracture, partially due to reduced osteoblastic bone formation. We reported that mesenchymal stem cells (MSCs) of TNF transgenic (TNF-Tg) mice, a model of RA, have significantly decreased osteoblast (obl) differentiation. The molecules that mediate inhibited obl function in RA are unknown and there is no effective therapy. To identify new molecules in MSCs that are responsible for obl inhibition, we performed a pathway analysis using data from RNA sequencing in purified MSCs of TNF-Tg mice and WT littermates. We found that the pathway involved in Notch is markedly up-regulated in TNF-Tg MSCs. In our preliminary study, we confirmed increased Notch in MSCs from TNF-Tg RA mice and RA patients. We found that intermittent Notch inhibition prevented bone loss in TNF-Tg mice and TNF activates Notch via non- canonical NF-?B p52&RelB protein. Based on these new findings, we hypothesize that in RA MSCs, TNF activates Notch signaling through non-canonical NF-?B p52&RelB, leading to a blockade of obl differentiation. Intermittent Notch inhibition prevents bone loss in TNF-Tg mice while continuous Notch inhibition exacerbates bone loss due to depletion of the MSC pools. These hypotheses will be tested in 3 specific aims.
In aim 1, we will determine if CD45-Hes1+ cells from Hes1-GFP mice functions as Notch-reporter MSCs. We will examine changes of function and Notch activation status in Hes1+MSCs from different ages of Hes1-GFP/TNF-Tg mice during the course of RA development.
In aim 2, we will use biochemical and molecular approaches to study mechanisms by which canonical NF-?B p52&RelB, as well as canonical NF-?B p50&RelA mediate the effect of TNF on Notch activation and if this is through the canonical Notch signaling pathway.
In aim 3, we will determine if intermittent, but not continues, administration of Notch inhibitor rescues bone loss phenotype of TNF-Tg mice and if increased Notch activation and inhibited obls in TNF-Tg mouse MSCs are mediated by TNF using TNF inhibitor. Our study will reveal a novel role for Notch in mediating RA-associated bone loss and interaction between non-canonical NF-?B and Notch, and generate preclinical information on Notch inhibitors as a new potential therapy for treating patients with RA or other chronic inflammation-associated osteoporosis.
Approximately 2.1 million people in the United States have rheumatoid arthritis (RA), a disease characterized by joint inflammation, bone destruction, and severe osteoporosis. This research proposal is aimed to study the role of mesenchymal stem cells, cells that give rise to bone forming cells, in the development of osteoporosis in RA by examining if Notch, a family of proteins that control the fate of stem cells, plays a role in development of osteoporosis-like symptoms in a mouse model of RA. Results from this study may lead to the development of new drug targets to prevent and treat patients with osteoporosis in RA.
|Boyce, Brendan F; Li, Jinbo; Xing, Lianping et al. (2018) Bone Remodeling and the Role of TRAF3 in Osteoclastic Bone Resorption. Front Immunol 9:2263|
|Sun, Wen; Meednu, Nida; Rosenberg, Alexander et al. (2018) B cells inhibit bone formation in rheumatoid arthritis by suppressing osteoblast differentiation. Nat Commun 9:5127|
|Paine, Ananta; Woeller, Collynn F; Zhang, Hengwei et al. (2018) Thy1 is a positive regulator of osteoblast differentiation and modulates bone homeostasis in obese mice. FASEB J 32:3174-3183|
|Li, Xing; Sun, Wen; Li, Jinbo et al. (2017) Clomipramine causes osteoporosis by promoting osteoclastogenesis via E3 ligase Itch, which is prevented by Zoledronic acid. Sci Rep 7:41358|
|Huang, Qi-Quan; Birkett, Robert; Doyle, Renee E et al. (2017) Association of Increased F4/80high Macrophages With Suppression of Serum-Transfer Arthritis in Mice With Reduced FLIP in Myeloid Cells. Arthritis Rheumatol 69:1762-1771|
|Xu, Hao; Bouta, Echoe M; Wood, Ronald W et al. (2017) Utilization of longitudinal ultrasound to quantify joint soft-tissue changes in a mouse model of posttraumatic osteoarthritis. Bone Res 5:17012|
|Wang, Wensheng; Wang, Hua; Zhou, Xichao et al. (2017) Lymphatic Endothelial Cells Produce M-CSF, Causing Massive Bone Loss in Mice. J Bone Miner Res 32:939-950|
|Sun, Wen; Zhang, Hengwei; Wang, Hua et al. (2017) Targeting Notch-Activated M1 Macrophages Attenuates Joint Tissue Damage in a Mouse Model of Inflammatory Arthritis. J Bone Miner Res 32:1469-1480|
|Lawal, Rialnat A; Zhou, Xichao; Batey, Kaylind et al. (2017) The Notch Ligand Jagged1 Regulates the Osteoblastic Lineage by Maintaining the Osteoprogenitor Pool. J Bone Miner Res 32:1320-1331|
|Li, Jinlong; Chen, Yan; Zhang, Li et al. (2016) Total saponins of panaxnotoginseng promotes lymphangiogenesis by activation VEGF-C expression of lymphatic endothelial cells. J Ethnopharmacol 193:293-302|
Showing the most recent 10 out of 21 publications