Inhibition of MAT2A suppresses osteoclastogenesis and prevents ovariectomy‐induced bone loss

Abstract

Methionine adenosyltransferase II alpha (MAT2A) is the key enzyme to transform methionine and adenosine‐triphosphate (ATP) to S‐adenosylmethionine (SAM), a general methyl‐group donor in vitro. MAT2A has been reported to participate in the NF‐κB pathway and maintain the methylated modification, which also affects osteoclastogenesis. In this study, we found the expression of MAT2A was increased upon RANKL stimulation. Pharmacological inhibition of MAT2A by its selective inhibitor AG‐270 or genetic silencing by MAT2A‐shRNA suppressed osteoclast formation and function in vitro. In vivo treatment with the inhibitor AG‐270 also prevented OVX‐induced bone loss. Further study revealed that the inhibition of MAT2A affected osteoclast differentiation mainly by suppressing crucial transcription factors and reactive oxygen species induced by RANKL. A quasi‐targeted metabolomics assay performed by LC‐MS/MS indicated that SAM was reduced by MAT2A knockdown, and the administration of SAM partly rescued the effects of MAT2A inhibition on osteoclastogenesis. These findings revealed that MAT2A is crucial for osteoclastogenesis and might be a potential target for the treatment of osteoporosis attributed to osteoclast dysfunction.

Application of metabolomics in osteoporosis research

“…Abnormal metabolism of valine might serve as a key mechanism of OP (31,38,75) relationship between OP and amino acid metabolism was further explored. The results of the study indicate that the change of the metabolite glutamate may play an important role in the pathogenesis of OP (26,36,70).…”

“…There is increasing evidence that some of the causative factors are modifiable risk factors for OP, such as abnormal drug intake, high fat, and abnormal hormone levels. Studies have shown that these substances can induce secondary OP by regulating changes in metabolite levels (32)(33)(34)(35)(36)(37)(38).…”

“…In addition, some recent studies have also suggested that the following amino acids may be closely related to the pathogenesis of OP, including: alanine ( 30 , 36 , 75 ), tryptophan ( 34 , 38 , 72 ), methionine ( 36 , 38 , 70 ), phosphatidylserine ( 67 , 68 ), urea ( 28 , 30 ), glycine ( 69 , 73 , 75 ), threonine ( 69 , 70 ), leucine ( 69 , 75 ), proline ( 31 , 70 , 75 ), aspartic acid ( 36 , 75 ), hydroxyproline ( 31 , 72 ), taurine ( 31 , 71 , 73 ), glutamine ( 31 , 75 ), as shown in Table 2 .…”

Inhibition ofFAAHsuppressesRANKL‐induced osteoclastogenesis and attenuates ovariectomy‐induced bone loss partially through repressing theIL17pathway

“…F‐actin ring staining and pit formation assays were performed as described earlier to analyze the effect of FAAH inhibition on osteoclast function 30 . Briefly, BMMs were cultured on 0.2% collagen‐gel coated 6‐well plates with M‐CSF (30 ng/ml) and RANKL (75 ng/ml) until osteoclasts formed.…”

“…F-actin ring staining and pit formation assays were performed as described earlier to analyze the effect of FAAH inhibition on osteoclast function. 30 Briefly, BMMs were cultured on 0.2% collagen-gel coated 6-well plates with M-CSF (30 ng/ml) and RANKL (75 ng/ml) until osteoclasts formed. Subsequently, RANKL-induced mature osteoclasts were digested with type I collagenase (0.2%) and reseeded in Corning osteo assay strip wells, and stimulated with different concentrations of PF (0, 0.25, 0.5, 1, and 2.5 μM) or infected with the lentivirus carrying FAAH-specific shRNA or the control lentivirus for an additional 3 days in the presence of 75 ng/ml RANKL.…”