Browsing by Author "Tak, Landon Y."

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    A moderate spinal contusion injury in rats alters bone turnover both below and above the level of injury with sex-based differences apparent in long-term recovery
    (Elsevier, 2024-04-10) Metzger, Corinne E.; Moore, Robert C.; Pirkle, Alexander S.; Tak, Landon Y.; Rau, Josephina; Bryan, Jessica A.; Stefanov, Alexander; Allen, Matthew R.; Hook, Michelle A.; Anatomy, Cell Biology and Physiology, School of Medicine
    Spinal cord injury (SCI) leads to significant sublesional bone loss and high fracture rates. While loss of mechanical loading plays a significant role in SCI-induced bone loss, animal studies have demonstrated mechanical loading alone does not fully account for loss of bone following SCI. Indeed, we have shown that bone loss occurs below the level of an incomplete moderate contusion SCI, despite the resumption of weight-bearing and stepping. As systemic factors could also impact bone after SCI, bone alterations may also be present in bone sites above the level of injury. To examine this, we assessed bone microarchitecture and bone turnover in the supralesional humerus in male and female rats at two different ages following a moderate contusion injury in both sub-chronic (30 days) and chronic (180 days) time points after injury. At the 30-day timepoint, we found that both young and adult male SCI rats had decrements in trabecular bone volume at the supralesional proximal humerus (PH), while female SCI rats were not different from age-matched shams. At the 180-day timepoint, there were no statistical differences between SCI and sham groups, irrespective of age or sex, at the supralesional proximal humerus. At the 30-day timepoint, all SCI rats had lower BFR and higher osteoclast-covered trabecular surfaces in the proximal humerus compared to age-matched sham groups generally matching the pattern of SCI-induced changes in bone turnover seen in the sublesional proximal tibia. However, at the 180-day timepoint, only male SCI rats had lower BFR at the supralesional proximal humerus while female SCI rats had higher or no different BFR than their age-matched counterparts. Overall, this preclinical study demonstrates that a moderate contusion SCI leads to alterations in bone turnover above the level of injury within 30-days of injury; however male SCI rats maintained lower BFR in the supralesional humerus into long-term recovery. These data further highlight that bone loss after SCI is not driven solely by disuse. Additionally, these data allude to potential systemic factors exerting influence on bone following SCI and highlight the need to consider treatments for SCI-induced bone loss that impact both sublesional and systemic factors.
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    Two Weeks of Continuous Opioid Treatment in an Adenine-Induced Mouse Model of Chronic Kidney Disease Exacerbates the Bone Inflammatory State and Increases Osteoclasts
    (Springer, 2024) Metzger, Corinne E.; Grecco, Gregory G.; Tak, Landon Y.; Atwood, Brady K.; Allen, Matthew R.; Anatomy, Cell Biology and Physiology, School of Medicine
    Patients with chronic kidney disease (CKD) report high pain levels, but reduced renal clearance eliminates many analgesic options; therefore, 30-50% of CKD patients have chronic opioid prescriptions. Opioid use in CKD is associated with higher fracture rates. Opioids may directly alter bone turnover directly through effects on bone cells and indirectly via increasing inflammation. We hypothesized that continuous opioid exposure would exacerbate the high bone turnover state of CKD and be associated with elevated measures of inflammation. Male C57Bl/6J mice after 8 weeks of adenine-induced CKD (AD) and non-AD controls (CON) had 14-day osmotic pumps (0.25-µL/hr release) containing either saline or 50-mg/mL oxycodone (OXY) surgically implanted in the subscapular region. After 2 weeks, all AD mice had elevated blood urea nitrogen, parathyroid hormone, and serum markers of bone turnover compared to controls with no effect of OXY. Immunohistochemical staining of the distal femur showed increased numbers of osteocytes positive for the mu opioid and for toll-like receptor 4 (TLR4) due to OXY. Osteocyte protein expression of tumor necrosis factor-α (TNF-α) and RANKL were higher due to both AD and OXY so that AD + OXY mice had the highest values. Trabecular osteoclast-covered surfaces were also significantly higher due to both AD and OXY, resulting in AD + OXY mice having 4.5-fold higher osteoclast-covered surfaces than untreated CON. These data demonstrate that opioids are associated with a pro-inflammatory state in osteocytes which increases the pro-resorptive state of CKD.