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

Abstract

Sickle cell disease (SCD) is the most common hereditary blood disorder in the United States. SCD is frequently associated with osteonecrosis, osteoporosis and osteopenia and other bone related complications such as vaso-occlusive pain, ischemic damage, osteomyelitis, and bone marrow hyperplasia known as sickle bone disease (SBD)1,2. 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 study the pathophysiological complications of SBD in both SCD and sickle cell trait. Changes in bone microarchitecture and bone development were assessed by high-resolution quantitative micro-computed tomography (microCT) and the 3D reconstruction of femurs from male and female mice. Our results indicate that SCD causes bone loss and sex-dependent anatomical changes in bone. Particularly, SCD female mice are prone to trabecular bone loss while cortical bone degradation occurs in both sexes. Additionally, we describe the impact of genetic knockdown of cathepsin K and E-64 mediated cathepsin inhibition on SBD.

A study of the influence of genetic variance and sex on the density and thickness of the calvarial bone in collaborative cross mice

“…On the other hand, other studies have claimed to demonstrate a significant interaction between sex and specific loci associated with BMD in humans 27–29 . In laboratory animals, there are many examples of genes that have a sex‐specific skeletal role 30–33 . In the past, we described the sex‐specific skeletal roles of Lef1 31 and Krox20 in mice 30,34 .…”

“…[27][28][29] In laboratory animals, there are many examples of genes that have a sex-specific skeletal role. [30][31][32][33] In the past, we described the sex-specific skeletal roles of Lef1 31 and Krox20 in mice. 30,34 In the latter case, the sexual dimorphism was associated with epigenetic changes that sex-specifically suppressed the role of genes involved in skeletal homeostasis.…”

A bone to pick-cellular and molecular mechanisms of bone pain in sickle cell disease

“…Animal studies show increased marrow osteoclast precursors numbers and activity which is responsible for bone loss (13). In addition, defective terminal osteoblast differentiation results in poor bone formation (13)(14)(15)(16). Markers of increased osteoclast activity such as tartrate-resistant acid phosphatase (TRAP) type 5b, have also been observed in sera of individuals with SCD (17)(18)(19).…”

“…Mechanistically, decreased bone strength results from loss of cortical, trabecular, and abnormal bone matrix composition known as bone quality ( 32 ). In two separate studies, the authors show femurs from sickle mice required less force to deform and had lower capacity to sustain high mechanical stress suggesting increased fragility and risk for fractures ( 14 , 15 ). As in humans, there is a lack of correlation with BMD.…”