Scientific Publications by FDA Staff

Pharmacol Res Perspect 2015 Oct;3(5):e00169

Modeling effects of dexamethasone on disease progression of bone mineral density in collagen-induced arthritic rats.

Lon HK, DuBois DC, Earp JC, Almon RR, Jusko WJ

A mechanism-based model was developed to characterize the crosstalk between proinflammatory cytokines, bone remodeling biomarkers, and bone mineral density (BMD) in collagen-induced arthritic (CIA) rats. Male Lewis rats were divided into five groups: healthy control, CIA control, CIA receiving single 0.225 mg kg(-1) subcutaneous (SC) dexamethasone (DEX), CIA receiving single 2.25 mg kg(-1) SC DEX, and CIA receiving chronic 0.225 mg kg(-1) SC DEX. The CIA rats underwent collagen induction at day 0 and DEX was injected at day 21 post-induction. Disease activity was monitored throughout the study and rats were sacrificed at different time points for blood and paw collection. Protein concentrations of interleukin (IL)-1beta, IL-6, receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), and tartrate-resistant acid phosphatase 5b (TRACP-5b) in paws were measured by enzyme-linked immunosorbent assays (ELISA). Disease progression and DEX pharmacodynamic profiles of IL-1beta, IL-6, RANKL, and OPG were fitted simultaneously and parameters were sequentially applied to fit the TRACP-5b and BMD data. The model was built according to the mechanisms reported in the literature and modeling was performed using ADAPT 5 software with naive pooling. Time profiles of IL-1beta and IL-6 protein concentrations correlated with their mRNAs. The RANKL and OPG profiles matched previous findings in CIA rats. DEX inhibited the expressions of IL-1beta, IL-6, and RANKL, but did not alter OPG. TRACP-5b was also inhibited by DEX. Model predictions suggested that anti-IL-1beta therapy and anti-RANKL therapy would result in similar efficacy for prevention of bone loss among the cytokine antagonists.