Mutations in COMP (cartilage oligomeric matrix protein) cause severe long bone shortening in mice and humans. Previously, we showed that massive accumulation of misfolded COMP in the ER of growth plate chondrocytes in our MT-COMP mouse model of pseudoachondroplasia (PSACH) causes premature chondrocyte death and loss of linear growth. Premature chondrocyte death results from activation of oxidative stress and inflammation through the CHOP-ER pathway and is reduced by removing CHOP or by anti-inflammatory or antioxidant therapies. Although the mutant COMP chondrocyte pathologic mechanism is now recognized, the effect of mutant COMP on bone quality and joint health (laxity) is largely unknown. Applying multiple analytic approaches, we describe a novel mechanism by which the deleterious consequences of mutant COMP retention results in upregulation of miR-223 disturbing the adipogenesis - osteogenesis balance. This results in reduction in bone mineral density, bone quality, mechanical strength and subchondral bone thickness. These, in addition to abnormal patterns of ossification at the ends of the femoral bones likely contribute to precocious osteoarthritis (OA) of the hips and knees in the MT-COMP mouse and PSACH. Moreover, joint laxity is compromised by abnormally thin ligaments. Altogether, these novel findings align with the PSACH phenotype of delayed ossification and bone age, extreme joint laxity and joint erosion, and extend our understanding of the underlying processes that affect bone in PSACH. These results introduce a novel finding that miR-223 is involved in the ossification defect in MT-COMP mice making it a therapeutic target.

Mechanical characterization of the intervertebral disc involves labor-intensive and destructive experimental methodology. Contrast-enhanced micro-computed tomography is a nondestructive imaging modality for high-resolution visualization and glycosaminoglycan quantification of cartilaginous tissues. The purpose of this study was to determine whether anionic and cationic contrast-enhanced micro-computed tomography of the intervertebral disc can be used to indirectly assess disc mechanical properties in an ex vivo model of disc degeneration. L3/L4 motion segments were dissected from female Lewis rats. To deplete glycosaminoglycan, samples were treated with 0 U/ml (Control) or 5 U/ml papain. Contrast-enhanced micro-computed tomography was performed following incubation in 40% Hexabrix (anionic) or 30 mg I/ml CA (cationic) for 24 h (n = 10/contrast agent/digestion group). Motion segments underwent cyclic mechanical testing to determine compressive and tensile modulus, stiffness, and hysteresis. Glycosaminoglycan content was determined using the dimethylmethylene blue assay. Correlations between glycosaminoglycan content, contrast-enhanced micro-computed tomography attenuation, and mechanical properties were assessed via the Pearson correlation. The predictive accuracy of attenuation on compressive properties was assessed via repeated random sub-sampling cross validation. Papain digestion produced significant decreases in glycosaminoglycan content and corresponding differences in attenuation and mechanical properties. Attenuation correlated significantly to glycosaminoglycan content and to all compressive mechanical properties using both Hexabrix and CA . Predictive linear regression models demonstrated a predictive accuracy of attenuation on compressive modulus and stiffness of 79.8-86.0%. Contrast-enhanced micro-computed tomography was highly predictive of compressive mechanical properties in an ex vivo simulation of disc degeneration and may represent an effective modality for indirectly assessing disc compressive properties. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2030-2038, 2018.

Objective: Assess acute alterations in bone turnover, microstructure, and histomorphometry following noninvasive anterior cruciate ligament rupture (ACLR).Methods: Twelve female Lewis rats were randomized to receive noninvasive ACLR or Sham loading (n=6/group). In vivo μCT was performed at 3, 7, 10, and 14 days post-injury to quantify compartmentdependent subchondral (SCB) and epiphyseal trabecular bone remodeling. Near-infrared (NIR) molecular imaging was used to measure in vivo bone anabolism (800 CW BoneTag) and catabolism (Cat K 680 FAST). Metaphyseal bone remodeling and articular cartilage morphology was quantified using ex vivo μCT and contrast-enhanced µCT, respectively. Calcein-based dynamic histomorphometry was used to quantify bone formation. OARSI scoring was used to assess joint degeneration, and osteoclast number was quantified on TRAP stained-sections.Results: ACLR induced acute catabolic bone remodeling in subchondral, epiphyseal, and metaphyseal compartments. Thinning of medial femoral condyle (MFC) SCB was observed as early as 7 days postinjury, while lateral femoral condyles (LFC) exhibited SCB gains. Trabecular thinning was observed in MFC epiphyseal bone, with minimal changes to LFC. NIR imaging demonstrated immediate and sustained reduction of bone anabolism (~15-20%), and a ~32% increase in bone catabolism at 14 days, compared to contralateral limbs. These findings were corroborated by reduced bone formation rate and increased osteoclast numbers, observed histologically. ACLR-injured femora had significantly elevated OARSI score, cartilage thickness, and cartilage surface deviation. Conclusion:ACL rupture induces immediate and sustained reduction of bone anabolism and overactivation of bone catabolism, with mild-to-moderate articular cartilage damage at 14 days postinjury..

Context: Mass vaccination serves as a potential solution to combat the Coronavirus disease 2019 (COVID-19) pandemic, with vaccine hesitancy being a recognized impediment. Collection of data defining the characteristics of healthcare worker (HCW) attitudes towards the vaccine can provide insight into vaccine hesitancy.

Quantitative analyses of bone using micro-computed tomography (μCT) are routinely employed in preclinical research, and virtual image reorientation to a consistent reference frame is a common processing step. The purpose of this study was to quantify error introduced by common reorientation algorithms in μCT-based characterization of bone. Mouse and rat tibial metaphyses underwent μCT scanning at a range of resolutions (6-30 μm). A trabecular volume-of-interest (VOI) was manually selected. Image stacks were analyzed without rotation, following 45° In-Plane axial rotation, and following 45° Triplanar rotation. Interpolation was performed using Nearest-Neighbor, Linear, and Cubic interpolations. Densitometric (bone volume fraction, tissue mineral density, bone mineral density) and morphometric variables (trabecular thickness, trabecular spacing, trabecular number, structural model index) were computed for each combination of voxel size, rotation, and interpolation. Significant reorientation error was measured in all parameters, and was exacerbated at higher voxel sizes, with relatively low error at 6 and 12 μm (max. reorientation error in BV/TV was 2.9% at 6 μm, 7.7% at 12 μm and 36.5% at 30 μm). Considering densitometric parameters, Linear and Cubic interpolations introduced significant error while Nearest-Neighbor interpolation caused minimal error, and In-Plane rotation caused greater error than Triplanar. Morphometric error was strongly and intricately dependent on the combination of rotation and interpolation employed. Reorientation error can be eliminated by avoiding reorientation altogether or by "de-rotating" VOIs from reoriented images back to the original reference frame prior to analysis. When these are infeasible, reorientation error can be minimized through sufficiently high resolution scanning, careful selection of interpolation type, and consistent processing of all images. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2762-2770, 2018.