Bortezomib (Btz, VELCADE) is a FDA approved drug for the treatment of patients with multiple myeloma or mantle cell lymphoma who are resistant to other drugs. Mouse studies indicate that Btz is also a bone anabolic agent. However, serious side effects of Btz, such as peripheral neuropathy and thrombocytopenia, limit its clinical utilization. The goal of this application is to generate bone-targeted Btz conjugates and test thei bioactivities. This will be carried out by a new interdisciplinary team including a Bone Biologist (Xing) and Chemist (Boeckman). Two special aims are proposed.
In Aim 1, bone-targeted Btz conjugates will be designed and synthesized by conjugating Btz to a bisphosphonate (BP) residue using novel chemical linkers to generate BP-Btz conjugates (1A). If BP-Btz conjugates bind to bone matrix and inhibit osteoclast function will be examined in vitro using bone slices that have been pre-incubated with BP-Btz. The effects of BP-Btz conjugates on osteoblast differentiation will be examined (1B).
In Aim 2, the effects of BP-Btz conjugates on OVX-induced bone loss (2A) and aged related fracture nonunion (2B) will be examined in mouse models. The side effects of BP-Btz will be compared to those of Btz. The preliminary data indicated that our recently generated BP-Btz1 binds to bone slices and maintains its bioactivity of osteoclast inhibition and osteoblast stimulation in vitro, supporting the feasibility of the proposal. The application fits the R21 mechanism in 2 ways: 1) it is high risk because it is not known if our BP-Btz conjugates are functional in vivo and if they have lesser systemic adverse effects as expected; 2) it is highly reward because BP-Btz conjugates are proven working in vivo, it will have significant impact not only on patient treatment, but also on synthesizing other bone-targeted drugs using the new conjugation technology. Furthermore, this application brings in 2 well-established investigators from different research fields to work on a very important problem that otherwise cannot be solved by individual PIs.
Bone fractures affect million Americans each year and 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, but the Velcade has toxic side effects when it enters the bloodstream, limiting its broader use. Here, we propose making a new form of Velcade, which will only act on bone, thereby reducing side effects, and we will test this new form of Velcade in mice with osteoporosis and bone fractures. If successful, our study will provide a new drug for patients with fractures and other bone-related diseases such as multiple myeloma, tumor metastasized to bone and osteoporosis.
| 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 |
| 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 |
| 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 |
