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Author Notes:

Edward A. Botchwey, The Parker H. Petit Institute for Bioengineering & Bioscience, 315 Ferst Dr NW, Atlanta, GA 30332; E-mail: edward.botchwey@bme.gatech.edu

J.S. and H.S. designed and performed experiments, collected and analyzed data, and wrote the manuscript; C.R. performed the microCT analysis; S.D. performed the osteoclast western blots, cathepsin zymography, and data analysis; A.A. and K.B. analyzed data; N.T. edited the manuscript; and E.A.B. and M.O.P. served as principal advisors and contributed to experimental design and manuscript editing.

The authors thank Georgia Tech Petit Institute for Bioengineering and Bioscience core facility managers, Steven Woodard, Angela Lin, and Sommer Durham, and all the animal facility staff.

The authors declare no competing financial interests.


Research Funding:

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


  • Science & Technology
  • Life Sciences & Biomedicine
  • Hematology
  • PAIN
  • MASS

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


Journal Title:



Volume 6, Number 5


, Pages 1381-1393

Type of Work:

Article | Final Publisher PDF


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.

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© 2022 by The American Society of Hematology

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/rdf).
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