Quantitative in vivo micro-computed tomography for monitoring disease activity and treatment response in a collagen-induced arthritis mouse model

Abstract

A painful, chronic condition, Rheumatoid Arthritis, is marked by bone erosion and soft tissue swelling at the joint. As treatments are investigated in pre-clinical models, characterizing disease progression is integral to assessing treatment efficacy. Here, in vivo and ex vivo micro-computed tomography (µCT) are used in parallel with traditional caliper score measurement to quantify physiological changes in the tarsal region in a murine, collagen-induced arthritis model. In vivo imaging methods, which are validated here through comparison to ex vivo and caliper methods, afford longitudinal analysis of both bone and soft tissue through a single image acquisition. This method removes the subjectivity of swelling quantification which is inherently associated with traditional caliper measurements. Histopathology offers an additional assessment of bone erosion and inflammation by providing a microscopic characterization of disease activity. In comparison to untreated animals, daily prednisolone (glucocorticoid) treatment is shown to restore bone volume, as reflected through in vivo and ex vivo µCT images, as well as histopathology. Prednisolone-associated reduction in inflammation is shown through in vivo µCT soft tissue volume measurements, paw caliper measurements, and histopathology. The findings reported here provide a comprehensive validation of in vivo µCT with a sensitivity that enables characterization of pre-clinical disease assessment in response to treatment in a murine, collagen-induced arthritis model.

Increased Imaging Ligand Hydrophilicity and Improved Pharmacokinetic Properties Provides Enhanced In Vivo Targeting of Fibroblast Activation Protein

“…The CIA murine model of RA was used to evaluate in vivo molecular imaging of FAP preclinically. After the rst symptoms of disease 51,52 , paw tissues were collected at 7 d, 14 d, and 21 d with corresponding IHC to con rm disease progression (Fig. 5).…”

“…Collagen-induced-arthritis (CIA) was induced as described previously 52 . Six-to eight-week-old male DBA/1J mice were obtained from Jackson Labs (Bar Harbor, ME).…”

Acthar Gel Inhibits the Activation of CD4+ and CD8+ T Cells

“…Mice were given a subcutaneous injection of 10, 40, or 400 U/kg of Acthar (Mallinckrodt Pharmaceuticals, Bridgewater, NJ, USA), 0.6 or 1.2 mg/kg of synthetic ACTH 1–24 depot (Bachem Americas, Inc., Torrence, CA, USA), or saline (control), or a 5-mg/kg oral dose of prednisolone (Sigma-Aldrich, St. Louis, MO, USA). These doses were selected due to their established activity in rodent studies (Fiorucci et al, 2002 ; Huang et al, 2021 ; Lord et al, 2022 ). One hour later, mice received an intraperitoneal injection of 10 μg human anti-mouse anti-CD3 monoclonal antibody (HαM CD3 MAb; Clone#145-2C11; BioLegend) in saline to activate T cells.…”

Image Registration in Longitudinal Bone Assessment Using Computed Tomography

“…Musculoskeletal diseases are defined by the World Health Organization (WHO) as being of long duration, taking decades to progress and whose high prevalence presents an increasing burden on both the national and family economies [ 1 , 2 ]. Quantitatively assessing and tracking bone microstructure and bone mechanical properties can support diagnosis [ 3 ], monitoring [ 4 ], and establishment of treatment options [ 5 ]. To this end, 3D imaging modalities such as computed tomography (CT) and its related imaging techniques such as micro-computed tomography (microCT) [ 6 ], high-resolution peripheral quantitative computed tomography (HR-pQCT) [ 7 ], and cone-beam computed tomography (CBCT) [ 8 ] have been deployed.…”