NEDD4 family E3 ligases in osteoporosis: mechanisms and emerging potential therapeutic targets

Table 1 The functions, mechanisms, and potential drug targets of NEDD4 family in OP

Name	Functions	Mechanisms	Potential drug targets	Refs
Smurf1	Inhibits osteoblast differentiation	Degrades BMP/Smad signaling pathway molecules	miR-195-5p, miR-25, miR-503, miR-19b-3p, miR-672-5p, miR-15b, GapmeRs, B06 and B75 compunds, chalcone derivatives, LMCD1, melatonin	[65,66,67,68,69,70,71,72,73,74,75]
		Ubiquitinates JunB
		Attenuates JNK activation
Smurf2	Inhibits osteoblast differentiation	Ubiquitinates receptor of BMP and TGF‑β signaling pathway	Hakai, serine/threonine protein kinase Akt, miR-590-5p, miR-19b, miR-130a, lncRNA RAD51-AS1, TRAF4	[82,83,84,85,86,87,88]
WWP1	Negatively regulates bone homeostasis	Ubiquitinates molecules in BMP and TGF‑β signaling pathway	siRNA/NP complexes, miR-19b-3p, miR-142-5p, C3A DNA aptamer	[95,96,97,98]
		Repressed by Wnt/β-catenin signaling pathway	miR-19b	[85]
		Ubiquitinates JunB
WWP2	Positively regulates osteogenesis	Relieves autoinhibition	NDFIP1/2, Dvl2	[103, 104]
		Enhances Runx2 transactivation
ITCH	Bidirectionally regulates osteogenesis	Phosphorylates Dvl in Wnt/β signaling pathway	Circ-ITCH	[107]
		Degrades Smad1 in BMP signaling pathway
		Degrades JunB
		Deubiquitinates TRAF6
NEDD4	Positively regulates osteogenesis	Degrades pSMAD1	Unclear	Unclear
NEDD4L	Bidirectionally regulates osteogenesis	HuR-mediated upregulation of NEDD4L	lncRNA SNHG14	[117]
		miR-214-3p/NEDD4L pathway	MOP	[118]
		Degrades Smad2/3 and TβR-I receptor in BMP and TGF‑β pathway
		Activates Akt pathway

ISSN: 1749-799X