MicroRNA-29a Mitigates Subacromial Bursa Fibrosis in Rotator Cuff Lesion with Shoulder Stiffness.

Rotator cuff lesion with shoulder stiffness is a major cause of shoulder pain and motionlessness. Subacromial bursa fibrosis is a prominent pathological feature of the shoulder disorder. MicroRNA-29a (miR-29a) regulates fibrosis in various tissues; however, the miR-29a action to subacromial bursa fibrosis remains elusive. Here, we reveal that subacromial synovium in patients with rotator cuff tear with shoulder stiffness showed severe fibrosis, hypertrophy, and hyperangiogenesis histopathology along with significant increases in fibrotic matrices collagen (COL) 1A1, 3A1, and 4A1 and inflammatory cytokines, whereas miR-29a expression was downregulated. Supraspinatus and infraspinatus tenotomy-injured shoulders in transgenic mice overexpressing miR-29a showed mild swelling, vascularization, fibrosis, and regular gait profiles as compared to severe rotator cuff damage in wild-type mice. Treatment with miR-29a precursor compromised COL3A1 production and hypervascularization in injured shoulders. In vitro, gain of miR-29a function attenuated COL3A1 expression through binding to the 3'-untranslated region (3'-UTR) of COL3A1 in inflamed tenocytes, whereas silencing miR-29a increased the matrix expression. Taken together, miR-29a loss is correlated with subacromial bursa inflammation and fibrosis in rotator cuff tear with shoulder stiffness. miR-29a repressed subacromial bursa fibrosis through directly targeting COL3A1 mRNA, improving rotator cuff integrity and shoulder function. Collective analysis offers a new insight into the molecular mechanism underlying rotator cuff tear with shoulder stiffness. This study also highlights the remedial potential of miR-29a precursor for alleviating the shoulder disorder.

Sclerostin vaccination mitigates estrogen deficiency induction of bone mass loss and microstructure deterioration.

Sclerostin (SOST) is a Wnt signaling inhibitor detrimental to osteogenic differentiation and bone mineral acquisition. While control of SOST action delays the pathogenesis of skeletal disorders, the effects of SOST vaccination on the estrogen deficiency-induced bone deterioration remain elusive. In this study, we generated a SOST-Fc fusion protein which was composed of a SOST peptide Pro-Asn-Ala-Ile-Gly along with an IgG Fc fragment. SOST-Fc vaccination increased serum anti-SOST antibody levels and reduced serum SOST concentrations in mice. In vitro, anti-SOST serum attenuated the SOST-induced inhibition of osteogenic gene expression in osteoblast cultures. Administration with SOST-Fc increased serum levels of bone formation marker osteocalcin and alleviated the ovariectomy escalation of serum resorption markers CTX-1 and TRAP5b concentrations. It remarkably lessened the estrogen deficiency-mediated deterioration of bone mineral density, morphometric characteristics of trabecular bone, and mechanical strength of femurs and lumbar spines. The SOST-Fc-treated skeletal tissue exhibited moderate responses to the adverse actions of ovariectomy to bone mineral accretion, osteoclast surface, trabecular separation, and fatty marrow histopathology. SOST-Fc treatment increased serum osteoclast-inhibitory factor osteoprotegrin levels in conjunction with strong Wnt3a, ß-catenin, and TCF4 immunostaining in osteoblasts, whereas it weakened the estrogen deficiency enhancement of osteoclast-promoting factor receptor activator of nuclear factor-κB ligand. Taken together, blockade of SOST action by SOST-Fc vaccination sustains Wnt signaling, which harmonizes bone mineral accretion and resorption reactions and thereby ameliorates ovariectomy-induced bone loss. This study highlights SOST-Fc fusion protein as a new molecular therapeutic potential for preventing from osteoporotic disorders.

Increased expression of type 1 cannabinoid (CB1) receptor among patients with rotator cuff lesions and shoulder stiffness.

BACKGROUND: Shoulder stiffness is a disease manifested by pain, limited range of motion, and functional disability. The inflammatory and fibrosis processes play a substantial role in the pathogenesis of shoulder stiffness. The CB1 receptor has been recognized to mediate the processes of pathologic fibrosis. This study investigated the role of the CB1 pathway in pathogenesis of rotator cuff lesions with shoulder stiffness. METHODS: All of the patients undergoing repair surgery for rotator cuff lesions were recruited and subcategorized into subjects with and without shoulder stiffness. Reverse transcription-polymerase chain reaction assay was used to evaluate the expression level of CB1 and interleukin 1ß (IL-1ß) in the subacromial bursae, and enzyme-linked immunosorbent assay was used to measure the concentration of CB1 and IL-1ß in the subacromial fluid. Tenocytes treated with CB1 agonists and antagonists were also studied for the relationship of CB1 and the inflammatory cytokine IL-1ß. RESULTS: The patients with shoulder stiffness had higher messenger RNA (mRNA) expression (P = .040) and immunohistochemistry staining (P < .001) of CB1 in the subacromial bursa and higher CB1 concentration in the subacromial fluid (P = .008). Tenocytes treated with the CB1 agonist WIN 55,212-2 and antagonist AM251 showed increased expression of IL-1ß mRNA (P = .049) and suppressed expression of IL-1ß mRNA (P = .001), respectively. DISCUSSION: The CB1 pathway is involved in the pathogenesis of shoulder stiffness. It may be a promising target for the treatment of rotator cuff lesions with shoulder stiffness.

Long sleep duration associated with a higher risk of increased arterial stiffness in males.

STUDY OBJECTIVES: We aimed to examine the association between sleep duration and arterial stiffness among adults of different ages, because to date there has been only one study on this relationship, which was confined to middle-aged civil servants. DESIGN: Cross-sectional study. SETTING: A health examination center in National Cheng Kung University Hospital, Taiwan. PARTICIPANTS: A total of 3,508 subjects, age 20-87 y, were enrolled after excluding those with a history of cerebrovascular events, coronary artery disease, peripheral artery disease, and taking lipid-lowering drugs, antihypertensives, hypoglycemic agents, and anti-inflammatory drugs, from October 2006 to August 2009. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: SLEEP DURATION WAS CLASSIFIED INTO THREE GROUPS: short (< 6 h), normal (6-8 h) and long (> 8 h). Arterial stiffness was measured by brachial-ankle pulse-wave velocity (baPWV), and increased arterial stiffness was defined as baPWV ≥ 1400 cm/sec. The sleep duration was different for subjects with and without increased arterial stiffness in males, but not in females. In the multivariate analysis for males, long sleepers (odds ratio [OR] 1.75, P = 0.034) but not short sleepers (OR 0.98, P = 0.92) had a higher risk of increased arterial stiffness. In addition, age, estimated glomerular filtration rate, hypertension, diabetes, total cholesterol/high-density lipoprotein cholesterol ratio, cigarette smoking, and exercise were also independently associated factors. However, in females, neither short nor long sleep duration was associated with increased arterial stiffness. CONCLUSIONS: Long sleep duration was associated with a higher risk of increased arterial stiffness in males. Short sleepers did not exhibit a significant risk of increased arterial stiffness in either sex. CITATION: Tsai TC, Wu JS, Yang YC, Huang YH, Lu FH, Chang CJ. Long sleep duration associated with a higher risk of increased arterial stiffness in males. SLEEP 2014;37(8):1315-1320.