Background/Purpose: Joint pain is the primary reason individuals with arthritis seek medical care. Unfortunately, arthritic pain is difficult to treat and current treatments are fraught with undesirable side effects. It is commonly thought that pain is evoked by inflammation and / or joint damage, leading to a peripheral and central sensitization. However, the severity of pain often does not correlate well with these factors. We hypothesize that, while inflammation leads to sensitization of joint terminals, over time, changes occurring within the joint itself may contribute to the ongoing pain state. Therefore, our goal was to characterize the time-course of changes occurring within cortical and trabecular bone of the femur, tibia, and ankle joint of arthritic mice using μCT analysis. Further, we examined the ankle joint for the presence of nerve sprouting of sensory and sympathetic nerve fibers as it has been shown that this sprouting may contribute to ongoing pain in other musculoskeletal diseases.

Methods: Using the K/BxN serum transfer model of arthritis, we have shown that male C75Bl/6 mice develop clinical signs of arthritis accompanied by a robust tactile allodynia. Importantly, male, but not female mice, show tactile allodynia persisting beyond the resolution of inflammation. For this reason, bones of arthritic male and female mice were analyzed on days 0, 10, and 28. We quantified arthritis-induced changes in the femur, tibia, talus, and calcaneus. For trabecular bone, we determined trabecular bone mineral density (tBMD), percent bone volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp), the degree of anisotropy (DA); while for cortical bone, BMD (cBMD), cortical area (Ct.Ar), and cortical thickness (Ct.Th) were examined. Following μCT analyses, bones were decalcified, processed for immunohistochemistry as frozen sections and immunostained with anti-CGRP (peptidergic C-fibers), anti-NF200 (myelinated sensory fibers), anti-GAP43 (sprouted nerve fibers), anti-TH (sympathetic nerve fibers), and anti-CD68 (macrophages).

Results: In the distal femur and proximal tibia, arthritic mice showed decreased tBMD, BV/TV, Tb.N at day 28 as compared to age-matched naive mice. There were no major changes in the cortical bone of the femoral or tibial mid-diaphyses. In the talus, there were no significant changes in any trabecular bone parameters in female or male arthritic mice as compared to naïve. In the calcaneus, tBMD and BV/TV are significantly decreased in male and female arthritic animals as compared to naïve, with females showing greater bone loss at day 28. While there was no difference in Tb.Th or Tb.Sp, we found a significant decrease in Tb.N over time in arthritic females. In addition to these changes in bone parameters, a semi-quantitative analysis revealed greater density of CGRP+, TH+, NF200+, and GAP43+ innervation in ankles of male mice at day 28, relative to female animals.

Conclusion: Together, these results suggest that K/BxN serum transfer-induced arthritis results in sex-dependent changes in tactile allodynia, which are reflected in underlying differences in peripheral sensory innervation, but not bone loss.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/persistent-tactile-allodynia-in-male-arthritic-mice-is-accompanied-by-sprouting-of-sensory-and-sympathetic-nerve-fibers/