Title : Neuropeptide Y-based recombinant peptides improve bone loss in mice by regulating hematopoietic stem/progenitor cell mobilization
Hematopoietic stem/progenitor cell (HSPC) mobilization is an essential homeostatic process regulated by the interaction of cellular and molecular components in bone marrow niches. It has been shown by others that neurotransmitters released from the sympathetic nervous system regulate HSPC egress from bone marrow to peripheral blood. We have investigated the functional role of neuropeptide Y (NPY) on this process. NPY deficient mice had significantly impaired HSPC mobilization due to increased expression of HSPC maintenance factors by reduction of matrix metalloproteinase-9 (MMP-9) activity in bone marrow. Pharmacological or endogenous elevation of NPY led to decrease of HSPC maintenance factors expression by activating MMP-9 in osteoblasts, resulting in HSPC mobilization. Mice in which the Y1 receptor was deleted in osteoblasts did not exhibit HSPC mobilization by NPY. Furthermore, full-length NPY treatment in ovariectomized mice caused reduction of bone loss due to HSPC mobilization. These results suggest a new role of NPY on HSPC mobilization, as well as the potential therapeutic application of this neuropeptide for stem cell-based therapy.
Based on these concepts and findings, we were designed to search for more functional recombinant peptides from the full-length NPY with the capability to efficiently mobilize HSPCs and prevent bone loss in ovariectomized mice. Here, we demonstrate that new NPY peptides, recombined from cleavage of the full-length NPY, showed better functionality for HSPC mobilization than the full-length peptide. These recombinant peptides resulted in a greater efficiency of HSPC mobilization by decreasing HSPC maintenance factors. Furthermore, treatment with these peptides reduced the number of osteoclasts, and relieved the ovariectomy-induced bone loss in mice more effectively than did treatment with the full-length NPY. Therefore, these results suggest the useful role of new peptides recombined from full-length NPY for the treatment of osteoporosis.