Megan Badejo

 Introduction. The Female Athlete Triad Syndrome has hallmark conditions of caloric/dietary deficiency, functional amenorrhea, and low bone mineral density (BMD)¹. Focusing on the low bone mineral density condition, the syndrome affects female athletes in any sport at any level². The condition manifests as a metabolic imbalance caused by the low energy state. This leads to estrogen deficiency, which plays a major role in the disturbance of bone homeostasis^1,3. Without it, more osteoclasts avoid apoptosis and more osteoblasts enter apoptosis resulting in an osteoporotic state. Studies highlight that if you manipulate the microenvironment to upregulate the Wnt-beta catenin pathway you can optimize mesenchymal stem cell (MSC) differentiation to osteoblasts by transplanted or endogenous MSCs^{4,5,6, 7}. Several studies suggest that the increased osteoblasts that result from from the activation of the Wnt/beta-catenin pathway could mitigate bone loss⁶. Methods. In a calvarial model, holes were drilled into the skulls of 3 groups of mice, one without treatment, one that received MSCs only and another that received MSCs in addition to osteogenic microenvironmental enrichment (administration of Catalpol)⁶. In an ovariectomy model, 3 groups of mice received ovariectomy alone, received an ovariectomy with catalpol, and a sham surgery⁶. Both studies utilized a Cell Counting Kit-8 assay to follow the engraftment of the MSCs. Alkaline phosphatase (ALP) staining, ALP activity and Alizarin Red staining were done to see the effect of catalpol on osteogenesis of the MSCs⁶. Quantitative RT-PCR, western blotting and immunofluorescence were done to measure the expression of osteoblast-specific markers and Wnt/β-catenin signaling-related genes⁶. Results. Mice that did not receive MSCs or catalpol exhibited slowest bone regeneration in the calvarial defect model and decreased bone loss attenuation in the ovariectomy model. The researchers of this study found that catalpol increased the regenerative capacity of MSCs and attenuated the loss in osteoblast in the presence of estrogen deficiency⁶. This aligned with the increased amount of cytosolic and nuclear β-catenin detected in the MSCs⁶. Conclusions. Optimizing the microenvironment so that the Wnt/beta-catenin pathway functions maximally can be achieved through the addition of compounds like Catalpol. MSCs are capable of producing regenerative effects on their own, however, in the presence of microenvironment enhancers like Catalpol, the regenerative capacity significantly increases. These findings may provide new avenues for attaining effective therapy for patients with the low BMD condition in the Female Athlete Triad.

1. Loveless MB. Female athlete triad. Current Opinion in Obstetrics and Gynecology. 2017;29(5):301-305. doi:10.1097/gco.0000000000000396
2. Female Athlete Issues for the Team Physician. Current Sports Medicine Reports. 2018;17(5):163-171. doi:10.1249/jsr.0000000000000482.
3. Southmayd EA, Mallinson RJ, Williams NI, Mallinson DJ, Souza MJD. Unique effects of energy versus estrogen deficiency on multiple components of bone strength in exercising women. Osteoporosis International. 2016;28(4):1365-1376. doi:10.1007/s00198-016-3887-x.
4. Garg P, Mazur MM, Buck AC, Wandtke ME, Liu J, Ebraheim NA. Prospective Review of Mesenchymal Stem Cells Differentiation into Osteoblasts. Orthopaedic Surgery
5. Majidinia M, Aghazadeh J, Jahanban-Esfahlani R, Yousefi B. The roles of Wnt/β-catenin pathway in tissue development and regenerative medicine. Journal of Cellular Physiology. 2018;233(8):5598-5612. doi:10.1002/jcp.26265.
6. Zhu Y, Wang Y, Jia Y, Xu J, Chai Y. Catalpol promotes the osteogenic differentiation of bone marrow mesenchymal stem cells via the Wnt/β-catenin pathway. Stem Cell Research & Therapy. 2019;10(1). doi:10.1186/s13287-019-1143-y.
7. Fujita K, Roforth MM, Demaray S, et al. Effects of Estrogen on Bone mRNA Levels of Sclerostin and Other Genes Relevant to Bone Metabolism in Postmenopausal Women. The Journal of Clinical Endocrinology & Metabolism. 2014;99(1).