A novel endpoint for the assessment of chemotherapy-induced peripheral neuropathy in rodents: biomechanical properties of peripheral nerve.

Chemotherapy-induced peripheral neuropathy (CiPN) is a frequent adverse effect in patients and a leading safety consideration in oncology drug development. Although behavioral assessment and microscopic examination of the nerves and dorsal root ganglia can be incorporated into toxicity studies to assess CiPN risk, more sensitive and less labor-intensive endpoints are often lacking. In this study, rats and mice administered vincristine (75 µg kg-1  day-1 , i.p., for 10 days in rats and 100 µg kg-1  day-1 , i.p., for 11 days in mice, respectively) were employed as the CiPN models. Behavioral changes were assessed during the dosing phase. At necropsy, the sural or sciatic nerve was harvested from the rats and mice, respectively, and assessed for mechanical and histopathological endpoints. It was found that the maximal load and the load/extension ratio were significantly decreased in the nerves collected from the animals dosed with vincristine compared with the vehicle-treated animals (P < 0.05). Additionally, the gait analysis revealed that the paw print areas were significantly increased in mice (P < 0.01), but not in rats following vincristine administration. Light microscopic histopathology of the nerves and dorsal root ganglia were unaffected by vincristine administration. We concluded that ex vivo mechanical properties of the nerves is a sensitive endpoint, providing a new method to predict CiPN in rodent. Gait analysis may also be a useful tool in these pre-clinical animal models.

Correlation between µCT imaging, histology and functional capacity of the osteoarthritic knee in the rat model of osteoarthritis.

BACKGROUND: To acquire the most meaningful understanding of human arthritis, it is essential to select the disease model and methodology translatable to human conditions. The primary objective of this study was to evaluate a number of analytic techniques and biomarkers for their ability to accurately gauge bone and cartilage morphology and metabolism in the medial meniscal tear (MMT) model of osteoarthritis (OA). METHODS: MMT surgery was performed in rats to induce OA. A dynamic weight bearing system (DWB) system was deployed to evaluate the weight-bearing capacity of the front and hind legs in rats. At the end of a 10-week study cartilage pathology was evaluated by micro computed tomography (µCT), contrast enhanced µCT (EPIC µCT) imaging and traditional histology. Bone tissue was evaluated at the tibial metaphysis and epiphysis, including the subchondral bone. Histological techniques and dynamic histomorphometry were used to evaluate cartilage morphology and bone mineralization. RESULTS: The study results showed a negative impact of MMT surgery on the weight-bearing capacity of the operated limb. Surgery caused severe and extensive deterioration of the articular cartilage at the medial tibial plateau, as evidenced by elevated CTX-II in serum, EPIC µCT and histology. Bone analysis by µCT showed thickening of the subchondral bone beneath the damaged cartilage, loss of cancellous bone at the metaphysis and active osteophyte formation. CONCLUSIONS: The study emphasizes the need for using various methodologies that complement each other to provide a comprehensive understanding of the pathophysiology of OA at the organ, tissue and cellular levels. Results from this study suggest that use of histology, µCT and EPIC µCT, and functional DWB tests provide powerful combination to fully assess the key aspects of OA and enhance data interpretation.

Effect of antiresorptive and anabolic bone therapy on development of osteoarthritis in a posttraumatic rat model of OA.

INTRODUCTION: Osteoarthritis (OA) is a leading cause of disability, but despite the high unmet clinical need and extensive research seeking dependable therapeutic interventions, no proven disease-modifying treatment for OA is currently available. Due to the close interaction and interplay between the articular cartilage and the subchondral bone plate, it has been hypothesized that antiresorptive drugs can also reduce cartilage degradation, inhibit excessive turnover of the subchondral bone plate, prevent osteophyte formation, and/or that bone anabolic drugs might also stimulate cartilage synthesis by chondrocytes and preserve cartilage integrity. The benefit of intensive zoledronate (Zol) and parathyroid hormone (PTH) therapy for bone and cartilage metabolism was evaluated in a rat model of OA. METHODS: Medial meniscectomy (MM) was used to induce OA in male Lewis rats. Therapy with Zol and human PTH was initiated immediately after surgery. A dynamic weight-bearing (DWB) system was deployed to evaluate the weight-bearing capacity of the front and hind legs. At the end of the 10-week study, the rats were euthanized and the cartilage pathology was evaluated by contrast (Hexabrix)-enhanced µCT imaging and traditional histology. Bone tissue was evaluated at the tibial metaphysis and epiphysis, including the subchondral bone. Histological techniques and dynamic histomorphometry were used to evaluate cartilage morphology and bone mineralization. RESULTS: The results of this study highlight the complex changes in bone metabolism in different bone compartments influenced by local factors, including inflammation, pain and mechanical loads. Surgery caused severe and extensive deterioration of the articular cartilage at the medial tibial plateau, as evidenced by contrast-enhanced µCT and histology. The study results showed the negative impact of MM surgery on the weight-bearing capacity of the operated limb, which was not corrected by treatment. Although both Zol and PTH improved subchondral bone mass and Zol reduced serum CTX-II level, both treatments failed to prevent or correct cartilage deterioration, osteophyte formation and mechanical incapacity. CONCLUSIONS: The various methods utilized in this study showed that aggressive treatment with Zol and PTH did not have the capacity to prevent or correct the deterioration of the hyaline cartilage, thickening of the subchondral bone plate, osteophyte formation or the mechanical incapacity of the osteoarthritic knee.