Psoralen regulates bone degenerative diseases by inhibiting APP phosphorylation to regulate MAPK and STAT3 signaling.

BACKGROUND

Psoralen can modulate bone metabolism pathways. This study investigated its effects on bone degenerative diseases, amyloid precursor protein (APP) phosphorylation, and the related pathways.

METHODS

The Aβ40/Aβ42 levels in mouse serum were analyzed through enzyme-linked immunosorbent assay (ELISA) across ages. mRNA levels of APP, APH-1α, PEN-2, and RAGE were determined through polymerase chain reaction (PCR). Thereafter, three degenerative models, including knee osteoarthritis, osteoporosis, and intervertebral disc degeneration, were established. Mice with APP knockout were generated, and the pathology was evaluated at weeks 4-20 through safranin O staining, osteoclast counting (immunohistochemistry, IHC), and hematoxylin and eosin (H&E) staining. Subsequently, TNF-α and HA contents were examined by ELISA, and Col2 expression and apoptosis were also analyzed. Furthermore, the anti-osteoporotic mechanisms of psoralen were explored at the cellular and animal levels.

RESULTS

As the mice aged, the expression of p-APP increased significantly, while that of proteins involved in the pathway decreased markedly. By constructing an APP knockout mouse model, it was found that after APP knockout, the mice developed bone degenerative lesions, which intensified with age. Intervention with psoralen was effective for ameliorating the pathologic condition of bone degenerative lesions in mice, and inhibiting the progression of bone tissue pathology. Notably, this effect exhibited a dose-dependent trend. Besides, intervention with psoralen in osteoblasts promoted osteoblast proliferation and regulated the phosphorylation of MAPK, AKT, and STAT3. For osteoblasts treated with pathway inhibitors and psoralen, psoralen exerted its effects through the MAPK, AKT, and STAT3 signaling pathways.

CONCLUSION

The phosphorylation of APP promotes the occurrence and progression of bone degenerative diseases. Psoralen regulates bone degenerative diseases by inhibiting APP phosphorylation, and regulating the MAPK and STAT3 signaling pathways.