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Rabbit lumbar FSUs were mounted in a bioreactor within a robotic testing system. FSUs underwent small (0.17\/0.05\u2009Nm) and large (0.5\/0.15\u2009Nm) range\u2010of\u2010motion F\/E for 1 or 2\u2009h of cycling. Outcomes in each tissue, compared to unloaded FSUs, included (i) relative mRNA expression of catabolic (<jats:italic>MMP\u20101, 3<\/jats:italic> and <jats:italic>ADAMTS\u20105<\/jats:italic>), pro\u2010inflammatory (<jats:italic>COX\u20102<\/jats:italic>), and anabolic (<jats:italic>ACAN<\/jats:italic>) genes and (ii) immunoblotting of aggrecan degradation. Total energy applied to FSUs increased in groups subject to large range\u2010of\u2010motion and 2\u2010h cycling, and moment relaxation was higher with large range\u2010of\u2010motion. F\/E significantly modulated <jats:italic>MMP1,\u20103<\/jats:italic> and <jats:italic>COX\u20102<\/jats:italic> in facet cartilage and <jats:italic>MMP\u20103<\/jats:italic> and <jats:italic>ACAN<\/jats:italic> in annulus fibrosus. Large range\u2010of\u2010motion loading increased MMP\u2010mediated aggrecan fragmentation in annulus fibrosus. Biological responses to complex loading ex vivo showed variation among spinal tissues that reflect tissue structure and mechanical loading in F\/E. \u00a9 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. 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