miRNA-27a is essential for bone remodeling by modulating p62-mediated osteoclast signaling
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Curated by eLife
Evaluation Summary:
The authors show that MiR-27a affects osteoclast-mediated bone resorption but not osteoblast-mediated bone formation during skeletal remodeling. Through gene profiling and bioinformatics study authors also identify the specific target of miR-27a in the osteoclast gene. MiR-27a exerts its effects on osteoclast differentiation through modulation of P62. This paper is of interest to scientists within the field of bone biology. The manuscript data analysis and conclusion are clear and directly supporting the previous known findings.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Abstract
The ability to simultaneously modulate a set of genes for lineage-specific development has made miRNA an ideal master regulator for organogenesis. However, most miRNA deletions do not exhibit obvious phenotypic defects possibly due to functional redundancy. miRNAs are known to regulate skeletal lineages as the loss of their maturation enzyme Dicer impairs bone remodeling processes. Therefore, it is important to identify specific miRNA essential for bone homeostasis. We report the loss of MIR27a causing severe osteoporosis in mice. MIR27a affects osteoclast-mediated bone resorption but not osteoblast-mediated bone formation during skeletal remodeling. Gene profiling and bioinformatics further identify the specific targets of MIR27a in osteoclast cells. MIR27a exerts its effects on osteoclast differentiation through modulation of Squstm1/p62 whose mutations have been linked to Paget’s disease of bone. Our findings reveal a new MIR27a-p62 axis necessary and sufficient to mediate osteoclast differentiation and highlight a therapeutic implication for osteoporosis.
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Evaluation Summary:
The authors show that MiR-27a affects osteoclast-mediated bone resorption but not osteoblast-mediated bone formation during skeletal remodeling. Through gene profiling and bioinformatics study authors also identify the specific target of miR-27a in the osteoclast gene. MiR-27a exerts its effects on osteoclast differentiation through modulation of P62. This paper is of interest to scientists within the field of bone biology. The manuscript data analysis and conclusion are clear and directly supporting the previous known findings.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
Wang et al. suggested that the most prominent gene downregulated in postmenopausal osteoporosis patients is miR-27a. Data suggested that removing miR27a resulted in considerable bone loss due to disturbed remodeling. Their findings further imply that miR-27a is unnecessary for osteoblast differentiation and bone formation. This work presents good data to show that miR-27a is necessary for controlling bone resorption. The deletion of miR-27a in mice increases the number of osteoclast cells as well as key parameters for bone resorption. As a result, directing miR-27a to bone resorption surfaces using synthetic drugs such as bisphosphonates or osteoclast-targeted molecules such as acid octapeptides containing aspartic acid can be crucial therapeutics for future use and miRNAs can very well be the next wave of …
Reviewer #1 (Public Review):
Wang et al. suggested that the most prominent gene downregulated in postmenopausal osteoporosis patients is miR-27a. Data suggested that removing miR27a resulted in considerable bone loss due to disturbed remodeling. Their findings further imply that miR-27a is unnecessary for osteoblast differentiation and bone formation. This work presents good data to show that miR-27a is necessary for controlling bone resorption. The deletion of miR-27a in mice increases the number of osteoclast cells as well as key parameters for bone resorption. As a result, directing miR-27a to bone resorption surfaces using synthetic drugs such as bisphosphonates or osteoclast-targeted molecules such as acid octapeptides containing aspartic acid can be crucial therapeutics for future use and miRNAs can very well be the next wave of future therapeutics.
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Reviewer #2 (Public Review):
In this study, authors showed that MiR-27a affects osteoclast-mediated bone resorption but not osteoblast-mediated bone formation during skeletal remodeling. Through gene profiling and bioinformatics study authors also identify the specific target of miR-27a in the osteoclast gene. MiR-27a exerts its effects on osteoclast differentiation through modulation of P62. The authors suggested the possible therapeutic use of the miR27a-p62 axis for the treatment of osteoporosis. This study is well designed and presented in a systematic manner. Findings have novelty and contribute significantly to the area of bone biology research.
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Reviewer #3 (Public Review):
The authors show miR-23a and miR-27a as an important regulator of bone homeostasis. They observed that miR 23a and miR27a regulates osteoclast function and loss of miR 23a and miR27a causes severe osteopenia conditions in mice without affecting osteoblast function. It has been already reported that miR27a regulates osteoclast function and inhibits osteoclast mediated bone resorption and F action formation (Guo L, et al). But the novelty of this manuscript is that single deletion of miR27a causes severe osteoporosis without affecting cortical bone. Reports suggest that p62 is an important regulator of osteoclastogenesis and deficiency of p62 impaired osteoclast differentiation. In paper, authors established a link between miR27a and p62 in osteoclast cells which could be a potential target for treatment of …
Reviewer #3 (Public Review):
The authors show miR-23a and miR-27a as an important regulator of bone homeostasis. They observed that miR 23a and miR27a regulates osteoclast function and loss of miR 23a and miR27a causes severe osteopenia conditions in mice without affecting osteoblast function. It has been already reported that miR27a regulates osteoclast function and inhibits osteoclast mediated bone resorption and F action formation (Guo L, et al). But the novelty of this manuscript is that single deletion of miR27a causes severe osteoporosis without affecting cortical bone. Reports suggest that p62 is an important regulator of osteoclastogenesis and deficiency of p62 impaired osteoclast differentiation. In paper, authors established a link between miR27a and p62 in osteoclast cells which could be a potential target for treatment of bone related disorders. Importantly, the mechanism of miR27a-p62 is not well explored in osteoclast cells.
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