Sickle cell disease promotes sex-dependent pathological bone loss through enhanced cathepsin proteolytic activity in mice

• Type of Material: Article
• Authors: Jeda Selma, Georgia Institute of Technology; Hannah Song, Georgia Institute of Technology; Christian Rivera, Georgia Institute of Technology; Simone Douglas, Georgia Institute of Technology; Abhiramgopal Akella, Georgia Institute of Technology; Keval Bollavaram, Georgia Institute of Technology; Nishone Thompson, Georgia Institute of Technology; Manu Platt, Emory University; Edward Botchwey, Emory University
• Language: English
• Date: 2022-03-08
• Publisher: ELSEVIER
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by The American Society of Hematology
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1182/bloodadvances.2021004615
• Title of Journal or Parent Work: BLOOD ADVANCES
• Volume: 6
• Issue: 5
• Start Page: 1381
• End Page: 1393
• Grant/Funding Information: The work was supported by grants from the National Institutes of Health (NIH) (National Institute of Arthritis and Musculoskeletal and Skin Diseases, R01AR056445; National Institute of Dental and Craniofacial Research, R01DE019935), grants from the Department of Defense (W81XWH-10-1-0928, E.A.B.) and the NIH (National Heart, Lung, and Blood Institute, R56HL136210-01, M.O.P.), and by the American Heart Association Grant-in-Aid (17GRNT33710016, M.O.P.).; The study was in part supported by the Regenerative Engineering and Medicine Center’s “Georgia Partners in Regenerative Medicine” seed grants and the Marcus Center for Therapeutic Cell Characterization and Manufacturing (MC3 M) research grant (E.A.B.). It was also supported by the National Science Foundation grant NSF GRFP DGE-1148903, an NIH/National Institute of General Medical Sciences Cells and Tissue Engineering Biotechnology training grant (T32GM008433), and the Alfred P. Sloan graduate fellowship awarded to J.S
• Keywords: IRRADIATION; ADULTS; Science & Technology; MASS; INHIBITION; Life Sciences & Biomedicine; PAIN; Hematology; MINERAL DENSITY
• Research Categories: Engineering, Biomedical

Abstract

Sickle cell disease (SCD) is the most common hereditary blood disorder in the United States. SCD is frequently associated with osteonecrosis, osteoporosis, osteopenia, and other bone-related complications such as vaso-occlusive pain, ischemic damage, osteomyelitis, and bone marrow hyperplasia known as sickle bone disease (SBD). Previous SBD models have failed to distinguish the age- and sex-specific characteristics of bone morphometry. In this study, we use the Townes mouse model of SCD to assess the pathophysiological complications of SBD in both SCD and sickle cell trait. Changes in bone microarchitecture and bone development were assessed by using high-resolution quantitative micro–computed tomography and the three-dimensional reconstruction of femurs from male and female mice. Our results indicate that SCD causes bone loss and sex-dependent anatomical changes in bone. SCD female mice in particular are prone to trabecular bone loss, whereas cortical bone degradation occurs in both sexes. We also describe the impact of genetic knockdown of cathepsin K– and E-64–mediated cathepsin inhibition on SBD.