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Loss of myocyte enhancer factor 2 expression in osteoclasts leads to opposing skeletal phenotypes.

ABSTRACT: Osteoclasts are multinuclear cells that resorb bone. Osteoclast differentiation is regulated by multiple transcription factors which may be acting in a single or multiple factor complex to regulate gene expression. Myocyte enhancer factor 2 (MEF2) is a family of transcription factors whose role during osteoclast differentiation has not been well characterized. Because MEF2A and MEF2D are the family members most highly expressed during osteoclast differentiation, we created conditional knockout mice models for MEF2A and/or MEF2D. In vitro cultures of A- and D-KO osteoclasts were smaller and less numerous than wild type cultures, while AD-KO osteoclasts were almost completely devoid of TRAP positive mononuclear cells. Female A-KO mice are osteopetrotic while male A- and D-KO mice of either sex had no significant in vivo skeletal phenotype, suggesting a sex-specific regulation of osteoclasts by MEF2A. Lastly, in vivo male AD-KO mice are osteopenic, indicating while MEF2 is required for M-CSF and RANKL-stimulated osteoclastogenesis in vitro, osteoclasts can form in the absence of MEF2 in vivo via a RANKL-alternative pathway.

SUBMITTER: Blixt N

PROVIDER: S-EPMC7443313 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Loss of myocyte enhancer factor 2 expression in osteoclasts leads to opposing skeletal phenotypes.

Blixt Nicholas N Norton Andrew A Zhang Anqi A Aparicio Conrado C Prasad Hari H Gopalakrishnan Rajaram R Jensen Eric D ED Mansky Kim C KC

Bone 20200606

Osteoclasts are multinuclear cells that resorb bone. Osteoclast differentiation is regulated by multiple transcription factors which may be acting in a single or multiple factor complex to regulate gene expression. Myocyte enhancer factor 2 (MEF2) is a family of transcription factors whose role during osteoclast differentiation has not been well characterized. Because MEF2A and MEF2D are the family members most highly expressed during osteoclast differentiation, we created conditional knockout m ...[more]

PMID: 32512162

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Project description:BackgroundPremature ventricular contractions (PVCs) are common in the general population, and frequent PVCs may result in the poor quality of life or even the damage of cardiac function. We examined the efficacy and safety of a traditional Chinese medicine Wenxin Keli for the treatment of frequent PVCs among a relatively large Chinese cohort.MethodsWe performed a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. A total of 1200 eligible participants were randomly assigned in a ratio of 1:1 to receive Wenxin Keli or the placebo for 4 weeks. The primary and secondary endpoint was the change of PVC numbers and PVC-related symptoms after a 4-week treatment compared with baseline, respectively. In addition, vital signs, laboratory values, and electrocardiographic parameters were assessed in a safety analysis.ResultsAt the initial evaluation, no significant differences in the baseline characteristics were observed between the Wenxin Keli group and the placebo group. A smaller number of PVCs was observed after the 4-week treatment than at baseline, in both the Wenxin Keli group (5686 ± 5940 vs. 15,138 ± 7597 beats/d, P < 0.001) and the placebo group (10,592 ± 8009 vs. 14,529 ± 5929 beats/d, P < 0.001); moreover, the Wenxin Keli group demonstrated a significantly greater reduction in the frequency of PVCs than the placebo group (P < 0.001). In a full analysis set, patients in the Wenxin Keli group exhibited significantly higher total effective responses in the reduction of PVCs compared to those in the placebo group (83.8% vs. 43.5%,P < 0.001). The per-protocol analysis yielded similar results (83.0% vs. 39.3%,P < 0.001). Treatment with Wenxin Keli also demonstrated superior performance compared to the placebo with respect to PVC-related symptoms. No severe adverse effects attributable to Wenxin Keli were reported.ConclusionsWenxin Keli treatment effectively reduced the overall number of PVCs and alleviated PVC-related symptoms in patients without structural heart diseases and had no severe side effects.

Dataset Information

Loss of myocyte enhancer factor 2 expression in osteoclasts leads to opposing skeletal phenotypes.

Publications

Loss of myocyte enhancer factor 2 expression in osteoclasts leads to opposing skeletal phenotypes.

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