Abstract
Osteoporotic fracture is a major cause of morbidity in patients with systemic lupus erythematosus (SLE). Mice lacking Fc gamma receptor IIb (FcγRIIB) spontaneously develop lupus-like disease or SLE at 6-month-old. The aim of this study was to investigate whether FcγRIIB deletion induces osteopenia. μCT analysis indicated that deleting FcγRIIB did not affect cancellous bone microarchitecture in 3-month-old mice in which SLE had not yet developed. However, 6- and 10-month-old FcγRIIB−/− males that developed an SLE-like phenotype were osteopenic and FcγRIIB deletion resulted in decreased cancellous bone volume. Histomorphometry confirmed a significant decrease in cancellous bone volume in 6- and 10-month-old FcγRIIB−/− males. The osteoclast number was increased without any change in osteoblast number. In vitro assays indicated that deleting FcγRIIB increased osteoclast differentiation while alkaline phosphatase activity and mineralization were unaltered. These changes were associated with increases in steady-state mRNA levels for the osteoclast marker genes Trap and Ctsk. Moreover, FcγRIIB−/− mice had higher level of serum TNFα, a proinflammatory cytokine. A soluble TNFα receptor, etanercept, prevented cancellous bone loss in FcγRIIB−/− mice. Our results indicate that FcγRIIB indirectly regulates cancellous bone homeostasis following SLE development. FcγRIIB deletion induces inflammatory bone loss due to increased TNFα-mediated bone resorption without any change in bone formation in mice with SLE-like syndrome.
Highlights
Systemic autoimmune diseases with complex multifactorial etiologies including systemic lupus erythematosus (SLE) are associated with low bone mass and fracture
To determine whether FcγRIIB deletion affected cancellous bone homeostasis in 3-month-old mice, we examine the skeletal phenotype of 3-monthold FcγRIIB−/− and FcγRIIB+/− males and their wild type (WT) controls. μCT analysis revealed no difference in cancellous bone volume, trabecular thickness, trabecular number, trabecular separation, or SMI between groups (Fig. 1A,B)
Our results indicated that FcγRIIB deletion did not affect skeletal homeostasis at 3 months of age when SLE disease was not active
Summary
Systemic autoimmune diseases with complex multifactorial etiologies including systemic lupus erythematosus (SLE) are associated with low bone mass and fracture. FcγRIIB, a negative regulator of IC-triggered activation, is associated with susceptibility to autoimmune disease, SLE4,5 This inhibitory receptor functions to suppress the development of autoimmunity by regulating B-cell responses and effector cell activation[6]. Our previous study indicated that mice with an FcγRIIB deletion resulted in SLE active disease at 6 months old. The FcγRIIB−/− mice had cortical bone loss and decreased mechanical properties at 6 and 10 months old after the development of SLE or lupus disease[12]. Etanercept, a TNFα inhibitor, increased cancellous bone volume and trabecular thickness in FcγRIIB−/− mice. These data suggested that the absence of FcγRIIB induced inflammation and cancellous osteopenia in mice with lupus-like syndrome
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