Table 1 The various signaling pathways and regulatory mechanisms through which Bmal1 regulates bone and cartilage metabolism
Signaling pathways | Cells/disease models | Effects | References |
|---|---|---|---|
Wnt/β-catenin signaling pathway | Chondrocytes | Bmal1 knockdown activated β-catenin expression, downregulated GSK-3β expression, and stimulated an inflammatory response | |
BMSCs | Bmal1 suppressed Wnt/β-catenin pathway, negatively regulated the osteogenic differentiation ability of BMSCs | ||
Diabetic BMSCs | Bmal1 overexpression activated the Wnt/β-catenin signaling pathway and restored BMSC osteogenic capacity by suppressing GSK-3β to some extent | ||
NIH-3T3 cells | Bmal1 overexpression increased β-catenin expression and enhanced cell proliferation rate | ||
TGF-β/BMP signaling pathway | MC-3T3 cells | Bmal1 over expression upregulated BMP2, RUNX2, OC expression, promoted osteoblast differentiation | |
BMSCs | Bmal1 overexpression upregulated BMP2 expression, promoted osteogenic differentiation in BMSCs | ||
Osteoblasts | Bmal1 deficiency activated the BMP2/SMAD1 signaling pathway, increasing osteoblast activity in the cortical area of adult mice; BMAL1 is a transcriptional silencer of BMP2 by directly binding to the Bmp2 promoter | ||
Human articular chondrocytes | Bmal1 deficiency reduced the levels of phosphorylated SMAD2/3 but increased p-SMAD1/5 activity | ||
Ligament-derived and embryonic fibroblasts | Bmal1 knockdown upregulated osteogenic markers as well as TGF-β/BMP pathway signals, inducing endochondral ossification in heterotopic ossification of tendons and ligaments | ||
MAPK/ERK signaling pathway | Chronic sleep deprivation rats | Chronic sleep deprivation activated p-ERK expression, resulting in upregulation of MMP-1, -3, and -13, and temporomandibular joint damage | |
Mandibular condylar chondrocytes | Bmal1 inhibition activated ERK phosphorylation, while ERK inhibition did not affect Bmal1 expression; Bmal1 overexpression reversed temporomandibular joint osteoarthritis in rats | ||
NF-κB signaling pathway | Diabetic BMSCs | Bmal1 may rescue diabetic BMSC osteogenic function by inhibiting the NF-κB pathway to some extent | |
Chondrocytes | IL-1β reduced Bmal1 expression through NF-κB activation | ||
Hedgehog signaling pathway | Chondrocytes | BMAL1 directly bound to Ptch1 and Ihh promoter region to activate hedgehog pathway, regulating chondrogenesis and endochondral ossification of mandibular condylar cartilages | |
HIF-1α-VEGF signaling pathway | Chondrocytes | Bmal1 deficiency upregulated the expression of HIF1α, VEGF, MMP13 and RUNX2, leading to decrease of chondrocyte proliferation | |
TTK/MDM2/ H2Bub1 axis | MSCs | Bmal1 targeted the circadian-controlled gene TTK to phosphorylate MDM2 (murine double minute 2) and modulate H2Bub1 (one histone) levels to positively affect the osteogenic capacity of MSCs |
