Impaired skeletal muscle stem cell (MuSC) function has long been suspected to contribute to the pathogenesis of muscular dystrophy (MD). Here, we showed that defects in the endothelial cell (EC) compartment of the vascular stem cell niche in mouse models of Duchenne MD, laminin α2–related MD, and collagen VI–related myopathy were associated with inefficient mobilization of MuSCs after tissue damage. Using chemoinformatic analysis, we identified the 13–amino acid form of the peptide hormone apelin (AP-13) as a candidate for systemic stimulation of skeletal muscle ECs. Systemic administration of AP-13 using osmotic pumps generated a pro-proliferative EC-rich niche that supported MuSC function through angiocrine factors and markedly improved tissue regeneration and muscle strength in all three dystrophic mouse models. Moreover, EC-specific knockout of the apelin receptor led to regenerative defects that phenocopied key pathological features of MD, including vascular defects, fibrosis, muscle fiber necrosis, impaired MuSC function, and reduced force generation. Together, these studies provide in vivo proof of concept that enhancing endogenous skeletal muscle repair by targeting the vascular niche is a viable therapeutic avenue for MD and characterized AP-13 as a candidate for further study for the systemic treatment of MuSC dysfunction.

Erosive destruction of joint structures is a critical event in the progression of rheumatoid arthritis (RA), in which fibroblast-like synoviocytes (FLS) are the primary effectors. We previously reported that the ability of RA FLS to degrade extracellular matrix (ECM) components depends on the formation of actin-rich membrane protrusions, called invadosomes, through processes that remain elusive. 14-3-3η belongs to a family of scaffolding proteins involved in a wide range of cellular functions, and its expression is closely related to joint damage and disease activity in RA patients. In this study, we sought to assess the role of 14-3-3η in joint damage by examining its contribution to the invadosome formation phenotype of FLS. Using human primary FLS, we show that 14-3-3η expression is closely associated with their ability to form invadosomes. Furthermore, knockdown of 14-3-3η using shRNAs decreases the level of invadosome formation in RA FLS, whereas addition of the recombinant protein to FLS from healthy individuals promotes their formation. Mechanistic studies suggest that 14-3-3η regulates invadosome formation by increasing Snail expression, a mechanism that involves nuclear exclusion of the transcription repressor FOXO3. Our results implicate the 14-3-3η–FOXO3–Snail axis in promoting the aggressive ECM-degrading phenotype of RA FLS, and suggest a role for this scaffolding protein in cartilage degradation.

Background: Type IV superior labral anterior to posterior (SLAP) lesions, which are superior labral detachments associated with Bankart tears, are reported to occur in up to 25% of recurrent shoulder instability patients. However, the clinical implications of this finding are debatable. Purpose: To determine whether there are any functional differences between anterior instability patients with and without type IV SLAP lesions at the time of presentation and at short-term follow-up after surgical intervention. Study Design: Cohort study; Level of evidence, 2. Methods: A prospective, multicenter database was established to follow the clinical evolution of patients with shoulder instability. Patients were diagnosed as having a type IV SLAP lesion at the time of arthroscopic Bankart surgery (SLAP+). These patients were compared with a group of patients who simply had a Bankart lesion (SLAP–). The 2 groups had their functional outcomes (Western Ontario Shoulder Instability Index [WOSI]; Disability of the Arm, Shoulder, and Hand [QuickDASH]; and Walch-Duplay) compared prior to surgery and 1 year postoperatively. Results: A total of 103 subjects were included in the study; of these, 56 (43 men, 13 women) completed 1-year follow-up. Twenty-three subjects had a type IV SLAP tear, and most had this repaired along with their Bankart lesion. At baseline, SLAP+ subjects had inferior QuickDASH scores compared with SLAP– subjects (37.8 vs 29.0) as well as poorer pain subscores on both the WOSI and QuickDASH. At 1-year follow-up, however, there were no significant differences in any of the outcome measures. Conclusion: A type IV SLAP lesion can be expected in 22% of patients with recurrent shoulder instability. This finding implies that at baseline, the patient will have slightly worse functional scores related to pain. However, following surgical management of the labral pathology, these patients will have equivalent functional outcomes at short-term follow-up. Clinical Relevance: With surgical management of the superior and anteroinferior labrum, patients with type IV SLAP lesions will do as well as those with only Bankart tears. Thus, the presence of SLAP lesions should not alter the decision to provide surgical management and should not change the prognosis for a specific patient.

Knee osteoarthritis (OA) is a painful condition characterized by joint and bone changes. A growing number of studies suggest that these changes only partially explain the pain experienced by individuals with OA. The purpose of the current study was to evaluate if corticospinal and bulbospinal projection measurements were interrelated in patients with knee OA, and to explore the relationship between these neurophysiological measures and temporal summation (excitatory mechanisms of pain) on one hand, and clinical symptoms on the other. Twenty-eight (28) patients with knee OA were recruited. Corticospinal projections were measured using transcranial magnetic stimulation, while bulbospinal projections were evaluated with a conditioned pain modulation (CPM) protocol using a counter-irritation paradigm. Validated questionnaires were used to document clinical and psychological manifestations. All participants suffered from moderate to severe pain. There was a positive association between corticospinal excitability and the effectiveness of the CPM (r_s = 0.67, p = 0.01, n = 13). There was also a positive relationship between pain intensity and corticospinal excitability (r_s = 0.45, p = 0.03, n = 23), and between pain intensity and temporal summation (r_s = 0.58, p = 0.01, n = 18). The results of this study highlight some of the central nervous system changes that could be involved in knee OA and underline the importance of interindividual variability to better understand and explain the semiology and pathophysiology of knee OA.