The goal of the parent grant is to investigate the role of Notch signaling in inflammatory osteoporosis. We found that persistent activation of Notch in mesenchymal stem/progenitor cells limits their osteoblast (OB) differentiation potential and causes bone loss, which can be prevented by Notch inhibitors, DAPT and Thapsigarin [1]. Our findings suggest that Notch inhibitors could be used as bone anabolic agents. However, Notch inhibitors have severe adverse effects due to systemic distribution [2], limiting their use in common diseases such as osteoporosis. Thus, making bone targeted Notch inhibitors to reduce their systemic side effects will be a very attractive approach. In this revision, we will form a ne interdisciplinary team including a Bone Biologist (Dr. Xing, the PI of the parent grant) and Chemists (Dr. Boeckman, a co-PI of the revision; Dr. Ebetino, consultant of the revision) to design and synthesize bone targeted Bortezomib by conjugating it to a bisphosphonate using a novel carbamate linker that will release Bortezomib from the Bortezomib- bisphosphonate. Two special aims are proposed.
In aim 1, we will design and synthesize bone-targeted Bortezomib conjugates and in aim 2, we will examine the bioactivity of bone-targeted Bortezomib conjugates in OB cultures and in mouse fracture healing. If we are successful, we will use a similar approach to synthesize bone targeted Notch inhibitors to reduce their toxic effects in the treatment of inflammatory osteoporosis, a main goal of the parent grant, and perhaps in other bone loss related to inflammation. The application will also lead to new directions for both Drs. Xing and Boeckman's lab: understanding the role of the ubiquitin- proteasome system in bone fracture repair in the aged population with a focus on mesenchymal stem/progenitor cells (Xing's lab); and using a novel chemical linker in other drugs and compounds, which will open a new strategy of bone targeting chemistry (Boeckman's lab).

Public Health Relevance

Bone fractures affect 5 million Americans each year. Promoting fracture healing could reduce pain, complications and medical cost. We found that a drug called Velcade, used in the treatment of patients with multiple myeloma, can promote the healing of bone fractures in mice. However, Velcade has toxic side effects when it enters the bloodstream, which prevents its broader use. We propose making a new form of Velcade that will only act on bone, thereby reducing side effects. We will test this new Velcade in mice with bone fractures. If successful, our study will provide a new drug for patients with fractures and other bone-related diseases such as multiple myeloma and tumor metastasized to bone.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR063650-02S1
Application #
8891736
Study Section
Special Emphasis Panel (ZAR1-KM (M1))
Program Officer
Alekel, D Lee
Project Start
2012-09-01
Project End
2015-08-31
Budget Start
2015-04-23
Budget End
2015-08-31
Support Year
2
Fiscal Year
2015
Total Cost
$76,750
Indirect Cost
$26,750
Name
University of Rochester
Department
Pathology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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

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