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Objective. The concept that intraarticular crystals of uric acid by themselves trigger episodes of painful gouty arthritis is inconsistent with the clinical reality.Patients with large deposits of monosodium urate monohydrate (MSU) crystals (tophi) do not necessarily experience gouty attacks. In fact, it is the excessive consumption of food or alcohol that elicits the inflammation of the acute gout attack. The aim of this study was to identify the precise mechanism that initiates flares of gouty arthritis.Methods. Human peripheral blood mononuclear cells (PBMCs) and murine macrophages were stimulated in vitro with MSU, free fatty acids (FFAs), or both in combination. Thereafter, production of interleukin-1␤ (IL-1␤) and activation of caspase 1 were determined. Gouty arthritis was induced in mice with deficiencies in the genes for caspase 1, ASC, NALP3, or IL-1␤, and the lack of inflammasome activity during joint swelling or other joint pathologic features was investigated in these mice. Gout is a chronic inflammatory disease that is characterized by recurrent attacks of acute joint inflammation and is regarded as the prototypical crystalinduced arthropathy (1). It is unknown why only a small number of individuals with hyperuricemia develop gout, which is attributable to the deposition of monosodium urate (MSU) crystals in the joints, and why the attacks of inflammation in patients with gout are sporadic, despite continuous deposition of uric acid crystals in the joints. Results. MSU crystals had no biologic effects on

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Modified muscle use can result in muscle atrophy and impairment. We tested whether inflammatory cell concentrations correlate temporally with muscle impairment during modified loading periods. Rat hindlimbs were unloaded for 10 days followed by reloading. The density of neutrophils and ED1+ macrophages was significantly increased by 16.5- and 9.8-fold, respectively, after 1 day of reloading. ED2+ macrophage concentration was not significantly increased until 3 days of reloading. Maximal isometric tetanic tension (P(o); N/cm2) decreased during hindlimb suspension (HS), which was followed by a second drop in P(o) after 2 h of reloading. This latter loss in muscle force was uncoupled with the significant elevation in muscle inflammatory cell concentrations. Experiments where HS soleus muscles were incubated with caffeine revealed that at least 40% of the P(o) decrement at 2 h could be associated with a loss of efficiency of the excitation-contraction (E-C) coupling process. These data suggest that an important mechanism for the early loss in force is the inability to activate the contractile machinery likely caused by a failure in the E-C coupling process during the reloading period.

CD44 is a transmembrane protein that plays a role in cell-cell interactions and motility in a number of cell types. Cell-cell interactions are critical for myoblast differentiation and fusion but whether CD44 regulates myogenesis is unknown. Here, we show that CD44 plays a functional role in early myogenesis. Analyses of myofiber cross-sectional area, after local injury in mouse tibialis anterior (TA) muscles, revealed that growth was transiently delayed in the absence of CD44. A muscle-intrinsic role for CD44 is suggested as primary myoblasts from CD44(-/-) mice displayed attenuated differentiation and subsequent myotube formation at early times in a differentiation-inducing in vitro environment. Chemotaxis of CD44(-/-) myoblasts toward hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF) was totally abrogated, although expression of their respective receptors did not appear to differ from wild-type. Furthermore, motility of CD44(-/-) myoblasts was decreased at early stages of differentiation as determined by time-lapse microscopy. Wild-type myoblasts contained two subpopulations of slow- and fast-migrating cells, whereas CD44(-/-) myoblasts were composed predominantly of the slower migrating subpopulation. Taken together, these data suggest that myoblast migration and differentiation are closely linked and CD44 is a key regulator.