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BACKGROUND

Newswise — Ankylosing spondylitis (AS) is recognized as a long-term inflammatory disorder that leads to inflammation in the spine and joints, alongside abnormal bone growth. In previous studies, we reported that mesenchymal stem cells (MSCs) derived from individuals with AS demonstrated a remarkable inhibition in the formation of osteoclasts compared to those obtained from healthy donors. The mechanism through which MSCs from AS patients achieve this inhibition remains unclear.

AIM

To investigate the potential underlying mechanism by which MSCs from individuals with ankylosing spondylitis (AS-MSCs) inhibit osteoclastogenesis.

METHODS

We analysed fat mass and obesity-associated (FTO) protein levels in AS-MSCs and MSCs from healthy donors and investigated the effects and mechanism by which FTO in MSCs inhibits osteoclastogenesis by coculturing and measuring the levels of tartrate-resistant acid phosphatase, nuclear factor of activated T cells 1 and cathepsin K.

RESULTS

We found that FTO, an enzyme responsible for removing methyl groups from RNA, was more abundantly expressed in MSCs from AS patients than in those from healthy donors. Reducing FTO levels was shown to diminish the capacity of MSCs to inhibit osteoclast development. Further experimental results revealed that FTO affects the stability of the long non-coding RNA activated by DNA damage (NORAD) by altering its N6-methyladenosine methylation status. Deactivating NORAD in MSCs significantly increased osteoclast formation by affecting miR-4284, which could regulate the MSC-mediated inhibition of osteoclastogenesis reported in our previous research.

CONCLUSION

This study revealed elevated FTO levels in AS-MSCs and found that FTO regulated the ability of AS-MSCs to inhibit osteoclast formation through the long noncoding RNA NORAD/miR-4284 axis.

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Core Tip: This study explores how mesenchymal stem cells (MSCs) from ankylosing spondylitis (AS) patients inhibit osteoclastogenesis. We observed higher expression of fat mass and obesity-associated protein (FTO) in AS-MSCs compared to healthy controls. Reducing FTO expression diminished their osteoclast inhibitory effect. FTO regulates the long non-coding RNA activated by DNA damage (NORAD) by modulating its N6-methyladenosine methylation, and NORAD silencing increased osteoclast formation via miR-4284. These results highlight FTO as a key regulator of AS-MSC function and suggest the long noncoding RNA NORAD/miR-4284 axis as a novel mechanism of osteoclast inhibition in AS.

• Citation: Liu WJ, Wang JX, Li QF, Zhang YH, Ji PF, Jin JH, Zhang YB, Yuan ZH, Feng P, Wu YF, Shen HY, Wang P. Fat mass and obesity-associated protein in mesenchymal stem cells inhibits osteoclastogenesis via lnc NORAD/miR-4284 axis in ankylosing spondylitis. World J Stem Cells 2025; 17(3): 98911
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