| Autor: |
Jiang M; Center for Musculoskeletal Health, Department of Internal Medicine, The University of California at Davis Medical Center, Sacramento, CA, 95817, USA.; Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, 200025, Shanghai, China., Liu R; Department of Biochemistry and Molecular Medicine, The University of California at Davis Medical Center, Sacramento, CA, 95817, USA., Liu L; Center for Musculoskeletal Health, Department of Internal Medicine, The University of California at Davis Medical Center, Sacramento, CA, 95817, USA., Kot A; Center for Musculoskeletal Health, Department of Internal Medicine, The University of California at Davis Medical Center, Sacramento, CA, 95817, USA., Liu X; Center for Musculoskeletal Health, Department of Internal Medicine, The University of California at Davis Medical Center, Sacramento, CA, 95817, USA., Xiao W; Department of Biochemistry and Molecular Medicine, The University of California at Davis Medical Center, Sacramento, CA, 95817, USA., Jia J; Center for Musculoskeletal Health, Department of Internal Medicine, The University of California at Davis Medical Center, Sacramento, CA, 95817, USA., Li Y; Department of Biochemistry and Molecular Medicine, The University of California at Davis Medical Center, Sacramento, CA, 95817, USA., Lam KS; Department of Biochemistry and Molecular Medicine, The University of California at Davis Medical Center, Sacramento, CA, 95817, USA., Yao W; Center for Musculoskeletal Health, Department of Internal Medicine, The University of California at Davis Medical Center, Sacramento, CA, 95817, USA. yao@ucdavis.edu. |
| Abstrakt: |
Activation and migration of endogenous mesenchymal stromal cells (MSCs) are critical for bone regeneration. Here, we report a combinational peptide screening strategy for rapid discovery of ligands that not only bind strongly to osteogenic progenitor cells (OPCs) but also stimulate osteogenic cell Akt signaling in those OPCs. Two lead compounds are discovered, YLL3 and YLL8, both of which increase osteoprogenitor osteogenic differentiation in vitro. When given to normal or osteopenic mice, the compounds increase mineral apposition rate, bone formation, bone mass, and bone strength, as well as expedite fracture repair through stimulated endogenous osteogenesis. When covalently conjugated to alendronate, YLLs acquire an additional function resulting in a "tri-functional" compound that: (i) binds to OPCs, (ii) targets bone, and (iii) induces "pro-survival" signal. These bone-targeted, osteogenic peptides are well suited for current tissue-specific therapeutic paradigms to augment the endogenous osteogenic cells for bone regeneration and the treatment of bone loss. |
