Recombinant Human NGF Protein

Low back pain (LBP) is a highly prevalent and disabling condition whose initiating factors are poorly understood. It is known that psychological and physical stress is associated with LBP but the causal relationship, mechanisms, and mediators have not been elucidated, and a preclinical model enabling the investigation of causality and thereby critically contributing to clinical translation does not exist. In this study, we first established and characterized a myofascial LBP model in mice based on nerve growth factor (NGF) injection into the low back muscles. Second, we investigated the effect of 2 different stress paradigms on this mouse LBP model by applying the chronic unpredictable stress and vertical chronic restraint stress (vCRS) paradigms, to mimic psychological and psychophysical stress, respectively. In these studies, we combined longitudinal behavioral tests with gene and protein expression analysis in the muscle, dorsal root ganglia, and spinal cord. Nerve growth factor-induced LBP was characterized by long-lasting local and plantar mechanical hypersensitivity, cold hyperalgesia, decreased grip strength and wheel running activity, and time-dependent changes of neuropeptide and glial markers in the spinal cord. Interestingly, the exposure to chronic unpredictable stress slightly worsened pain behavior, whereas vCRS primed and highly aggravated pain in this LBP model, by causing per se the intramuscular upregulation of endogenous NGF and increased spinal astrocyte expression. Our mouse model, particularly the combination of NGF injection and vCRS, suggests that similar mechanisms are important in nonspecific LBP and might help to investigate certain aspects of stress-induced exacerbation of pain.

BackgroundOsteoarthritis is generally a slowly progressive disorder. However, at least 1 in 7 people with incident knee osteoarthritis develop an abrupt progression to advanced-stage radiographic disease, many within 12months. We summarize what is known - primarily based on findings from the Osteoarthritis Initiative - about the risk factors and natural history of accelerated knee osteoarthritis (AKOA) - defined as a transition from no radiographic knee osteoarthritis to advanced-stage disease <4years - and put these findings in context with typical osteoarthritis (slowly progressing disease), aging, prior case reports/series, and relevant animal models.SummaryRisk factors in the 2 to 4years before radiographic manifestation of AKOA (onset) include older age, higher body mass index, altered joint alignment, contralateral osteoarthritis, greater pre-radiographic disease burden (structural, symptoms, and function), or low fasting glucose. One to 2years before AKOA onset people often exhibit rapid articular cartilage loss, larger bone marrow lesions and effusion-synovitis, more meniscal pathology, slower chair-stand or walking pace, and increased global impact of arthritis than adults with typical knee osteoarthritis. Increased joint symptoms predispose a person to new joint trauma, which for someone who develops AKOA is often characterized by a destabilizing meniscal tear (e.g., radial or root tear). One in 7 people with AKOA onset subsequently receive a knee replacement during a 9-year period. The median time from any increase in radiographic severity to knee replacement is only 2.3years. Despite some similarities, AKOA is different than other rapidly progressive arthropathies and collapsing these phenomena together or extracting results from one type of osteoarthritis to another should be avoided until further research comparing these types of osteoarthritis is conducted. Animal models that induce meniscal damage in the presence of other risk factors or create an incongruent distribution of loading on joints create an accelerated form of osteoarthritis compared to other models and may offer insights into AKOA.ConclusionAccelerated knee osteoarthritis is unique from typical knee osteoarthritis. The incidence of AKOA in the Osteoarthritis Initiative and Chingford Study is substantial. AKOA needs to be taken into account and studied in epidemiologic studies and clinical trials.