Background: Osteopetrosis caused by mutation of Plekhm1 gene is characterized by malignant phenotypes, poor quality of life, and lack of effective treatment. It remains in dispute whether hematopoietic stem cell transplantation (HSCT) is a suitable therapeutic approach for it. In addition, other potential novel therapeutics including gene therapies have not yet been investigated for their efficacies. Materials and Methods: We generated an osteopetrotic mouse model caused by deficiency of Plekhm1 gene, and performed HSCT, ex vivo and in vivo gene therapies, respectively. Results: A notable reduction of femoral trabecular bone mass, along with osteoporosis, was observed after HSCT treatment for 12 weeks. For ex vivo gene therapy, HSCs of KO mice were explanted, transferred by LV- Plekhm1 , and reinfused into KO mice. After 12 weeks, osteopetrosis of Plekhm1 KO mice was also improved significantly. In vivo gene therapy was performed by injecting AAV- Plekhm1 into left tibial bone marrow cavity of KO mice. A significant reduction in the trabecular area of the left femora of Plekhm1 KO mice 12 weeks after treatment with AAV- Plekhm1 was observed. Conclusion: Both HSCT, ex vivo and in vivo gene therapies showed good safety profiles, which provides promising therapeutic approaches to potentially rescue the osteopetrotic phenotype in patients with a Plekhm1 gene mutation.

Background: The present definition of obesity based on body mass index (BMI) is not accurate and effective enough to identify hospitalized patients with a heavier burden, especially for postmenopausal hospitalized patients concomitant with osteoporosis. The link between common concomitant disorders of major chronic diseases such as osteoporosis, obesity, and metabolic syndrome (MS) remains unclear. Here, we aim to evaluate the impact of different metabolic obesity phenotypes on the burden of postmenopausal hospitalized patients concomitant with osteoporosis in view of unplanned readmissions. Methods: Data was acquired from the National Readmission Database 2018. The study population was classified into metabolically healthy non-obese (MHNO), metabolically unhealthy non-obese (MUNO), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO) patients. We estimated the associations between metabolic obesity phenotypes and 30- and 90-day unplanned readmissions. A multivariate Cox Proportional Hazards (PH) model was used to assess the effect of factors on endpoints, with results expressed as HR and 95% CI. Results: The 30-day and 90-day readmission rates for the MUNO and MUO phenotypes were higher than that of the MHNO group (all p < 0.05), whereas no significant difference was found between the MHNO and MHO groups. For 30-day readmissions, MUNO raised the risk mildly (hazard ratio [HR] = 1.110, p < 0.001), MHO had a higher risk (HR = 1.145, p = 0.002), and MUO further elevated this risk (HR = 1.238, p < 0.001). As for 90-day readmissions, both MUNO and MHO raised the risk slightly (HR = 1.134, p < 0.001; HR = 1.093, p = 0.014, respectively), and MUO had the highest risk (HR = 1.263, p < 0.001). Conclusions: Metabolic abnormalities were associated with elevated rates and risks of 30- or 90-day readmission among postmenopausal hospitalized women complicated with osteoporosis, whereas obesity did not seem to be innocent, and the combination of these factors led to an additional burden on healthcare systems and individuals. These findings indicate that clinicians and researchers should focus not only on weight management but also metabolism intervention among patients with postmenopausal osteoporosis.