RESUMEN
The chronic inflammation present in type 2 diabetes causes many chronic inflammatory comorbidities, including cardiovascular, renal, and neuropathic complications. Type 2 diabetes is also associated with a number of spinal pathologies, including intervertebral disc (IVD) degeneration and chronic neck and back pain. Although confounding factors such as obesity are thought to increase the loads to the musculoskeletal system and subsequent degeneration, studies have shown that even after adjusting age, body mass index, and genetics (e.g. twins), patients with diabetes suffer from disproportionately more IVD degeneration and back pain. Yet the tissue-specific responses of the IVD during diabetes remains relatively unknown. We hypothesize that chronic diabetes fosters a proinflammatory microenvironment within the IVD that accelerates degeneration and increases susceptibility to painful disorders. To test this hypothesis, we evaluated two commonly used mouse models of diabetes - the leptin-receptor deficient mouse (db/db) and the chronic high-fat diet in mice with impaired beta-cell function (STZ-HFD). The db/db is a genetic model that spontaneous develop diabetes through hyperphagia, while the STZ-HFD mouse first exhibits rapid obesity development under HFD and pronounced insulin resistance following streptozotocin administration. Both animal models were allowed to develop sustained diabetes for at least twelve weeks, as defined by elevated hemoglobin A1C, hyperglycemia, and glucose intolerance. Following the twelve-week period, the IVDs were extracted in quantified in several measures including tissue-specific secreted cytokines, viscoelastic mechanical behavior, structural composition, and histopathologic degeneration. Although there were no differences in mechanical function or the overall structure of the IVD, the STZ-HFD IVDs were more degenerated. More notably, the STZ-HFD model shows a significantly higher fold increase for eight cytokines: CXCL2, CCL2, CCL3, CCL4, CCL12 (monocyte/macrophage associated), IL-2, CXCL9 (T-cell associated), and CCL5 (pleiotropic). Correlative network analyses revealed that the expression of cytokines differentially regulated between the db/db and the STZ-HFD models. Moreover, the STZ-HFD contained a fragmented and modular cytokine network, indicating greater complexities in the regulatory network. Taken together, the STZ-HFD model of type 2 diabetes may better recapitulate the complexities of the chronic inflammatory processes in the IVD during diabetes.
RESUMEN
Inflammatory cytokine production and de novo neurovascularization have been identified in painful, degenerated intervertebral discs (IVDs). However, the temporal trajectories of these key pathoanatomical features, including the cascade of inflammatory chemokines and neo- vessel and neurite infiltration, and their associations with IVD degeneration, remain relatively unknown. Investigating this process in the caudal mouse IVD enables the opportunity to study the tissue-specific response without confounding inflammatory signaling from neighboring structures. Thus this study aims to define the progression of chemokine production and neurovascular invasion during the IVD degeneration initiated by injury in the caudal spine 3-month-old C57BL6/J mice. Forty-nine IVD-secreted chemokines and matrix metalloproteinases (MMPs) was measured using multiplex ELISA, and the intradiscal infiltrating vessels (endomucin) and nerves (protein-gene-product 9.5) was quantified in the tissue volume using immunohistochemistry. Injury provoked the increase secretion of IL6, CCL2, CCL12, CCL17, CCL20, CCL21, CCL22, CXCL2 and MMP2 proteins. The centrality and structure of inflammatory networks in IVDs evolved over the 12 post-injury weeks, highlighting distinct responses between the acute and chronic phases. Neurites propagated rapidly within 2-weeks post-injury and remained relatively constant until 12-weeks. Vascular vessel length was observed to peak at 4-weeks post-injury and it regressed by 12-weeks. These findings identified the temporal flux of inflammatory chemokines and pain-associated pathoanatomy in a model of IVD degeneration using the mouse caudal spine.
RESUMEN
Non-specific lower back pain (LBP) is a world-wide public health problem that affects people of all ages. Despite the high prevalence of non-specific LBP and the associated economic burdens, the pathoanatomical mechanisms for the development and course of the condition remain unclear. While intervertebral disc degeneration (IDD) is associated with LBP, there is overlapping occurrence of IDD in symptomatic and asymptomatic individuals, suggesting that degeneration alone cannot identify LBP populations. Previous work has been done trying to relate linear measurements of compression obtained from Magnetic Resonance Imaging (MRI) to pain unsuccessfully. To bridge this gap, we propose to use advanced non-Euclidean statistical shape analysis methods to develop biomarkers that can help identify symptomatic and asymptomatic adults who might be susceptible to standing-induced LBP. We scanned 4 male and 7 female participants who exhibited lower back pain after prolonged standing using an Open Upright MRI. Supine and standing MRIs were obtained for each participant. Patients reported their pain intensity every fifteen minutes within a period of 2 h. Using our proposed geodesic logistic regression, we related the structure of their lower spine to pain and computed a regression model that can delineate lower spine structures using reported pain intensities. These results indicate the feasibility of identifying individuals who may suffer from lower back pain solely based on their spinal anatomy. Our proposed spinal shape analysis methodology have the potential to provide powerful information to the clinicians so they can make better treatment decisions.