RSPO3 is a novel contraction-inducible factor identified in an "in vitro exercise model" using primary human myotubes.

The physiological significance of skeletal muscle as a secretory organ is now well known but we can only speculate as to the existence of as-yet-unidentified myokines, especially those upregulated in response to muscle contractile activity. We first attempted to establish an "insert-chamber based in vitro exercise model" allowing the miniature but high cell-density culture state enabling highly developed contractile human myotubes to be readily obtained by applying electric pulse stimulation (EPS). By employing this in vitro exercise model, we identified R-spondin 3 (RSPO3) as a novel contraction-inducible myokine produced by cultured human myotubes. Contraction-dependent muscular RSPO3 mRNA upregulation was confirmed in skeletal muscles of mice subjected to sciatic nerve mediated in situ contraction as well as those of mice after 2 h of running. Pharmacological in vitro experiments demonstrated a relatively high concentration of metformin (millimolar range) to suppress the contraction-inducible mRNA upregulation of human myokines including RSPO3, interleukin (IL)-6, IL-8 and CXCL1. Our data also suggest human RSPO3 to be a paracrine factor that may positively participate in the myogenesis processes of myoblasts and satellite cells. Thus, the "insert chamber-based in vitro exercise model" is a potentially valuable research tool for investigating contraction-inducible biological responses of human myotubes usually exhibiting poorer contractility development even in the setting of EPS treatment.

Joint hemorrhage accelerates cartilage degeneration in a rat immobilized knee model.

BACKGROUND: Joint hemorrhage is caused by trauma, ligament reconstruction surgery, and bleeding disorders such as hemophilia. Recurrence of hemorrhage in the joint space induces hemosiderotic synovitis and oxidative stress, resulting in both articular cartilage degeneration and arthropathy. Joint immobilization is a common treatment option for articular fractures accompanied by joint hemorrhage. Although joint hemorrhage has negative effects on the articular cartilage, there is no consensus on whether a reduction in joint hemorrhage would effectively prevent articular cartilage degeneration. The purpose of this study was to investigate the effect of joint hemorrhage combined with joint immobilization on articular cartilage degeneration in a rat immobilized knee model. METHODS: The knee joints of adult male rats were immobilized at the flexion using an internal fixator from 3 days to 8 weeks. The rats were randomly divided into the following groups: immobilized blood injection (Im-B) and immobilized-normal saline injection (Im-NS) groups. The cartilage was evaluated in two areas (contact and non-contact areas). The cartilage was used to assess chondrocyte count, Modified Mankin score, and cartilage thickness. The total RNA was extracted from the cartilage in both areas, and the expression of metalloproteinase (MMP)-8, MMP-13, interleukin (IL)-1ß, and tumor necrosis factor (TNF)-α was measured by quantitative real-time polymerase chain reaction. RESULTS: The number of chondrocytes in the Im-B group significantly decreased in both areas, compared with that in the Im-NS group. Modified Mankin score from 4 to 8 weeks of the Im-B group was significantly higher than that of the Im-NS group only in the contact area. The expression of MMP-8 and MMP-13 from 2 to 4 weeks and TNF-α from 2 to 8 weeks significantly increased in the Im-B group compared with those in the Im-NS group, but there was no significant difference in IL-1ß expression. CONCLUSIONS: The results showed that joint hemorrhage exacerbated immobilization-induced articular cartilage degeneration. Drainage of a joint hemorrhage or avoidance of loading may help prevent cartilage degeneration during joint immobilization with a hemorrhage.

Effects of joint capsular release on range of motion in patients with frozen shoulder.

BACKGROUND: A thickened joint capsule is believed to be one of the most specific manifestations of and the primary restraint against range of motion (ROM) in frozen shoulders. The purpose of this study was to evaluate the relationship among ROMs under general anesthesia before surgery and the effects of each joint capsular release on ROM. METHODS: ROM was measured using a goniometer with scapular fixation. Arthroscopic pan-capsular release was performed with the patient in the beach-chair position in the following order: (1) rotator interval, (2) coracohumeral ligament, (3) superior capsule, (4) middle glenohumeral ligament, (5) anterior inferior glenohumeral ligament, and (6) posterior inferior glenohumeral ligament. ROMs in forward flexion (FF), lateral elevation (LE), external rotation with the arm at the side (ER1), external rotation at 90° of LE (ER2), internal rotation at 90° of LE (IR2), horizontal flexion, external rotation at 90° of FF (ER3), and internal rotation at 90° of FF (IR3) were evaluated before and after each release. RESULTS: A total of 32 consecutive shoulders were included. After each capsular release, the ROM recovered; the final ROM was significantly greater on the affected side than on the unaffected side. Significant correlations were found between FF and LE, FF and ER1, ER1 and ER2, ER1 and ER3, ER2 and ER3, and IR2 and IR3 on both sides, regardless of surgery. CONCLUSION: Each segment of the joint capsule affected ROM in all directions, supporting the need for whole-joint capsular release; ROM was significantly greater on the affected side than on the unaffected side after surgery.

RAGE-dependent NF-kB inflammation processes in the capsule of frozen shoulders.

BACKGROUND: The etiology of frozen shoulder (FS) remains uncertain. Advanced glycation end-products (AGEs) cause the cross-linking and stabilization of collagen and are increased in FS. The purpose of this study was to elucidate the pathogenesis of FS by evaluating the receptor of AGE (RAGE)-dependent pathways. METHODS: Tissue samples of the coracohumeral ligament (CHL) and anterior inferior glenohumeral ligament (IGHL) were collected from 33 patients with FS, with severe stiffness, and 25 with rotator cuff tears (RCTs) as controls. Gene expression levels of RAGE, high-mobility group box 1 (HMGB1), Toll-like receptor 2 (TLR2), TLR4, nuclear factor-kappa B (NF-kB), and cytokines were evaluated using a quantitative real-time polymerase chain reaction. The immunoreactivities of carboxymethyllysine (CML), pentosidine, and RAGE were also evaluated. CML and pentosidine were further evaluated using high-performance liquid chromatography. RESULTS: Gene expression levels of RAGE, HMGB1, TLR2, TLR4, and NF-kB were significantly greater in the CHLs and IGHLs from the FS group than in those from the RCT group. Immunoreactivities of RAGE and CML were stronger in the CHLs and IGHLs from the FS group than in those from the RCT group. Pentosidine was weakly immunostained in the CHLs and IGHLs from the FS group. CML using high-performance liquid chromatography was significantly greater in the CHLs and IGHLs from the FS group than in those from the RCT group. CONCLUSIONS: AGEs and HMGB1 might play important roles in the pathogenesis of FS by binding to RAGE and activating NF-kB signaling pathways. Suppression of these pathways could be a treatment option for FS.

Restriction in the hip internal rotation of the stride leg is associated with elbow and shoulder pain in elite young baseball players.

BACKGROUND: Evidence is scarce concerning the relationship of physical dysfunction of the trunk and lower extremities with elbow and shoulder pain in young baseball players. This study aimed to examine the association of joint flexibility of the trunk and lower extremities and dynamic postural control with elbow and shoulder pain among elite young baseball players. METHODS: We analyzed baseball players (aged 9-12 years) who participated in the National Junior Sports Clubs Baseball Festival. Range of motion in external rotation and internal rotation (IR) of the hip, as well as the finger-to-floor distance and heel-to-buttock distance, was measured. The straight-leg-raise test was also conducted. Dynamic postural control was evaluated using the Star Excursion Balance Test. Multivariable logistic regression analyses were conducted to examine the association of physical function with the elbow or shoulder pain incidence. RESULTS: Of 210 players surveyed, 177 without elbow or shoulder pain were included in the analysis. Of the participants, 16 (9.0%) reported having elbow or shoulder pain during the tournament. Participants with the incidence of elbow or shoulder pain had a significant restriction in hip IR of the stride leg compared with those without pain (35.8° vs. 43.7°, P = .022). There were no significant associations of other joint flexibilities and the Star Excursion Balance Test with elbow or shoulder pain. CONCLUSION: Decreased hip IR range of motion of the stride leg was significantly associated with the elbow or shoulder pain incidence. Players, coaches, and clinicians should consider the physical function of the trunk and lower extremities for the prevention of elbow and shoulder pain.

Playing video games for more than 3 hours a day is associated with shoulder and elbow pain in elite young male baseball players.

BACKGROUND: The effect of lifestyle factors on elbow or shoulder pain in young baseball players remains unclear. This study examined the association of game playing and television viewing with elbow or shoulder pain among elite young baseball players. METHODS: Study participants were young baseball players (age, 9-12 years) who participated in the National Junior Sports Clubs Baseball Festival in 2017. The national tournament invited 16 teams (totaling 210 players) selected based on the results of the regional qualifying tournaments. Self-reported questionnaires were mailed to all players before the tournament. Multiple logistic regression analyses were used to assess the association of video game playing and television viewing behavior with elbow or shoulder pain. RESULTS: Among the 210 players polled, 200 male players were included in the analysis. The prevalence of elbow or shoulder pain was 30.0%. Playing video games for ≥3 hours/day was significantly associated with elbow or shoulder pain vs. spending <1 hour/day playing video games (odds ratio, 5.59; 95% confidence interval, 1.44-21.64; P = .013). The amount of time spent watching television was not significantly associated with the prevalence of elbow or shoulder pain. CONCLUSIONS: Playing video games for ≥3 hours/day was associated with elbow or shoulder pain among elite young male baseball players. These findings highlight the effect of lifestyle on elbow and shoulder pain and should be taken into consideration by players, coaches, parents, and clinicians for the prevention of elbow and shoulder pain.

A Thickened Coracohumeral Ligament and Superomedial Capsule Limit Internal Rotation of the Shoulder Joint: Report of Three Cases.

Adhesive capsulitis of the shoulder (also known as frozen shoulder) is a painful and disabling disorder with an estimated prevalence ranging from 2% to 5% in the general population. Although the precise pathogenesis of frozen shoulder is unclear, thickened capsule and coracohumeral ligament (CHL) have been documented to be one of the most specific manifestations. The thickened CHL has been understood to limit external rotation of the shoulder, and restriction of internal rotation of the shoulder has been believed to be related to posterior capsular tightness. In this paper, three cases of refractory frozen shoulder treated through arthroscopic release of a contracted capsule including CHL were reported. Two cases in which there is recalcitrant severe restriction of internal rotation after manipulation under anesthesia (MUA) were finally treated with arthroscopic surgery. Although MUA could release the posterior capsule, internal rotation did not improve in our cases. After release of the thickened CHL, range of motion of internal rotation was significantly improved. This report demonstrates the role of the thickened CHL in limiting the internal rotation of the shoulder. We highlight the importance of release of thickened CHL in addition to the pancapsular release, in case of severe limitation of internal rotation of shoulder.