Caspase‐2 deficiency protects mice from diabetes‐induced marrow adiposity

Abstract

Type I (T1) diabetes is an autoimmune and metabolic disease associated with bone loss. Bone formation and density are decreased in T1-diabetic mice. Correspondingly, the number of TUNEL positive, dying osteoblasts increases in bones of T1-diabetic mice. Moreover, two known mediators of osteoblast death, TNFα and ROS, are increased in T1-diabetic bone. TNFα and oxidative stress are known to activate caspase-2, a factor involved in the extrinsic apoptotic pathway. Therefore, we investigated the requirement of caspase-2 for diabetes-induced osteoblast death and bone loss. Diabetes was induced in 16-week old C57BL/6 caspase-2 deficient mice and their wild type littermates and markers of osteoblast death, bone formation and resorption, and marrow adiposity were examined. Despite its involvement in extrinsic cell death, deficiency of caspase-2 did not prevent or reduce diabetes-induced osteoblast death as evidenced by a twofold increase in TUNEL positive osteoblasts in both mouse genotypes. Similarly, deficiency of caspase-2 did not prevent T1-diabetes induced bone loss in trabecular bone (BV/TV decreased by 30 and 50%, respectively) and cortical bone (decreased cortical thickness and area with increased marrow area). Interestingly, at this age, differences in bone parameters were not seen between genotypes. However, caspase-2 deficiency attenuated diabetes-induced bone marrow adiposity and adipocyte gene expression. Taken together, our data suggest that caspase-2 deficiency may play a role in promoting marrow adiposity under stress or disease conditions, but it is not required for T1-diabetes induced bone loss.

Caspases in metabolic disease and their therapeutic potential

“…These studies indicate a potential role for caspase-2 as a target in obesity, however, as with the other caspases, it is yet to be established if blocking caspase-2 can reverse pre-existing disease. Interestingly, Casp2 −/− mice have also been shown to be protected from streptozocin diabetes-induced bone marrow adiposity [73] suggesting depot-specific differences.…”

Diabetes and Bone Marrow Adiposity

“…Although T1DM and T2DM have clear differences in pathophysiology and consequences, we will discuss specific potential mechanisms for increased marrow fat in the two diseases here, noting when a potential mechanism applies to just one disease or is shared. We focus on possible causal mechanisms and acknowledge that there may be other factors at play not discussed in this review, including oxidative stress [42], adiponectin, glucocorticoids, and sex hormones.…”

Caspase-2: the orphan caspase

“…A subsequent study showed that caspase-2 deficiency attenuated diabetes-induced bone marrow adiposity indicated by decreased PPARy, which is a marker for adipocyte differentiation, suggesting a potential role for caspsase-2 in adipocyte differentiation. 69 …”