HMGB1 and arthritic joint disease: Despite both male and female mice expressing spinal TLR4, intrathecal injection of the TLR4 ligand, lipopolysaccharide (LPS) induces hypersensitivity only in male mice.42 By contrast, others have shown that LPS injection into the spinal cord as well as administration into the cerebral ventricle and hind paw produces allodynia in both sexes.42,51 The role of peripheral HMGB1 and TLR4 in pain has never been examined carefully in experimental arthritis with respect to sex-dependent mechanisms.