Background: Osteoporosis is the most common metabolic bone disease. There is still an
unmet need for novel therapeutic agents that could be beneficial as osteoporosis treatments. It has
been reported that the neurotransmitter γ-aminobutyric acid (GABA) might be associated with human
bone formation. However, the precise mechanism remains unclear.
Objective: To investigate the effect of GABA on bone metabolism and explore the possible role of
TNFAIP3 in this process.
Methods: GABA had little effect on the proliferation of human mesenchymal stem cells (hMSCs) and
RAW 264.7 cells, as indicated by the cell counting kit-8 (CCK-8) assay. The results showed that
GABA enhanced the intensity of ALP staining, ALP activity, and accumulation of Ca2+ mineralized
nodules in hMSCs during osteogenic induction.
Results: The qRT-PCR results indicated that GABA treatment significantly increased the mRNA expression
of osteogenic genes in hMSCs. In RAW 264.7 cells, TRAP staining showed that GABA did not alter
the number or size of osteoclasts or the expression of osteoclastic genes, which suggests that GABA
does not affect osteoclastic differentiation. Mechanistically, GABA treatment significantly induced the
sustained expression of TNFAIP3. Furthermore, by knocking down TNFAIP3, the osteogenic effect of
GABA was antagonized, which suggests that TNFAIP3 mediates the effects of GABA in hMSCs.
Conclusion: Our results suggested that GABA treatment positively regulated osteogenic differentiation
by upregulating TNFAIP3, while no obvious effect on osteoclastic differentiation was detected.
Therefore, our results provide a potential gene therapy for the treatment of osteoporosis and low bone