July Jost

Introduction. Primary Osteoporosis (OP) is the most common bone disease worldwide and is characterized by an imbalance in bone homeostasis with a bone mineral density (BMD) 2.5 standard deviations below average^1,2. This increases the risk for fracture development^1,2. Declining levels of sex-steroids associated with menopause in women and aging in both sexes is a likely mechanism involved^3,4. Bisphosphonates are antiresorptive agents commonly prescribed for chronic treatment which poses risks for side-effects such as osteonecrosis⁵. The use of mesenchymal stem cells (MSCs) for connective tissue repair has been of recent focus for their self-renewing capabilities⁶. Stromal Cell Derived Factor-1 (SDF-1) is a chemokine secreted by many cell types including osteoblasts to recruit MSCs from the bone marrow (BM) to specific bone sites through binding the CXC Motif Chemokine Receptor 4 (CXCR4) on MSCs⁶. CXCR4 is a G-protein-coupled-receptor that upon activation, promotes MSC migration and differentiation⁶. Studies have found that this signaling axis can be altered in osteoporotic rats and may have potential in MSC-based therapies^{7,8, 9, 10, 11}. Methods. Rats were ovariectomized (OVX) to mimic the osteoporotic condition^{9, 10}. An adenoviral vector system was utilized to transfect OVX MSCs with the CXCR4 gene, which was transplanted in the rat BM^9,10. A boyden chamber with a SDF-1 gradient was used to assess MSC migration upon CXCR4 transfection^{7, 9, 10}. Another study utilized hydrogel technology to transplant MSCs into the BM of OVX rats with an 8-week continuous SDF-1 delivery and monitored bone deposition¹¹. Results. OVX promoted a downregulation in MSC CXCR4 expression levels and a decline in CXCR4 intracellular AKT signaling, which reduced overall MSC migration towards SDF-1⁷. Upregulating CXCR4 through transfection in OVX MSCs increased CXCR4 expression by 97.9%, which enhanced mean migration towards SDF-1 five-fold compared to the control⁹.  When injected intravenously, CXCR4 transfected MSCs localized to the blood vessels of trabecular bone in OVX-rats which improved L4 vertebral stiffness, bone volume (BV), BMD, and trabecular structure¹⁰. Transplantation of the hydrogel containing MSCs and SDF-1 improved overall bone formation, BMD, BV/TV ratio and trabecular thickness.¹¹ Interestingly, this was demonstrated alongside an increased recruitment of cells containing CXCR4 and an up-regulation in CXCR4 locally¹¹. Conclusions. Studies have found that osteoporotic rats demonstrate impaired MSC migration that may occur through a dysregulation in the SDF-1/CXCR4 homing pathway. Targeting this axis employing CXCR4-transfected MSCs or SDF-1 releasing-hydrogels may be an alternative avenue for enhancing the BM microenvironment in patients suffering from Primary OP.

1. Kanis JA on behalf of the World Health Organization Scientific Group.  Technical Report.World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield; UK: 2007. 2007. Assessment of osteoporosis at the primary health-care level.
2. Sozen T, Ozisik L, Basaran NC. An overview and management of osteoporosis. Eur J Rheumatol. Mar 2017;4(1):46-56. doi:10.5152/eurjrheum.2016.048
3. Khosla S, Oursler MJ, Monroe DG. Estrogen and the skeleton. Trends Endocrinol Metab. Nov 2012;23(11):576-81. doi:10.1016/j.tem.2012.03.008
4. Fariyike B, Singleton Q, Hunter M, et al. Role of MicroRNA-141 in the Aging Musculoskeletal System: A Current Overview. Mech Ageing Dev. Mar 2019;178:9-15. doi:10.1016/j.mad.2018.12.001
5. Phetfong J, Sanvoranart T, Nartprayut K, et al. Osteoporosis: the current status of mesenchymal stem cell-based therapy. Cell Mol Biol Lett. 2016;21:12. doi:10.1186/s11658-016-0013-1
6. Gilbert W, Bragg R, Elmansi AM, et al. Stromal cell-derived factor-1 (CXCL12) and its role in bone and muscle biology. Cytokine. Nov 2019;123:154783. doi:10.1016/j.cyto.2019.154783
7. Liu Q, Zhang X, Jiao Y, et al. In vitro cell behaviors of bone mesenchymal stem cells derived from normal and postmenopausal osteoporotic rats. Int J Mol Med. Feb 2018;41(2):669-678. doi:10.3892/ijmm.2017.3280
8. Periyasamy-Thandavan S, Burke J, Mendhe B, et al. MicroRNA-141-3p Negatively Modulates SDF-1 Expression in Age-Dependent Pathophysiology of Human and Murine Bone Marrow Stromal Cells. J Gerontol A Biol Sci Med Sci. Aug 16 2019;74(9):1368-1374. doi:10.1093/gerona/gly186
9. Sanghani-Kerai A, Coathup M, Samazideh S, et al. Osteoporosis and ageing affects the migration of stem cells and this is ameliorated by transfection with CXCR4. Bone Joint Res. Jun 2017;6(6):358-365.    doi:10.1302/2046-3758.66.BJR-2016-0259.R1
10. Sanghani A, Osagie-Clouard L, Samizadeh S, et al. CXCR4 Has the Potential to Enhance Bone Formation in Osteopenic Rats. Tissue Eng Part A. Dec 2018;24(23-24):1775-1783. doi:10.1089/ten.TEA.2018.0121
11. Liu Q, Wen Y, Qiu J, et al. Local SDF-1alpha application enhances the therapeutic efficacy of BMSCs transplantation in osteoporotic bone healing. Heliyon. Jun 2020;6(6):e04347. doi:10.1016/j.heliyon.2020.e04347