Table 2.

Action mechanism of PGRN in metabolic diseases related to bone homeostasis imbalance.

Target molecule	Way	Molecular mechanism	Result	Disease	Refs
PGRN	OB differentiation	PGRN activated ERK1/2 and MAPK phosphorylation, and promoted ob differentiation and proliferation. Ko-PGRN caused BV/TV, N.Ob/BS, MAR and BFR were significantly increased, but there was no change in male mice	Promote or inhibit bone formation	OP	(104, 105)
	OC differentiation	PGRN upregulated the levels of p-PERK, p-eIF2α and ATF4, activated the PERK/p-eIF2α signalling pathway, and inhibited OC activity. Serum PGRN can promote the expression of TRAP, NFATc1 and OSCAR, increase the number of TRAP+MNCs and promote the differentiation of OC by up regulating the expression of PIRO	Promote or inhibit bone resorption		(33, 109)
	OB-OC coupling	PGRN increased E2 level, and PGRN+E2 up-regulated the expression of OB related markers Runx2, OPG, DMP1, and down regulated the expression of OC related markers NFATc1, ACP5, CTSK. GRN gene up regulates the expression of GRN mRNA and OC markers CTSK, ACP5, TRAP, Csf1r, Adgre1 and C1q.	The absence of GRN inhibits the maturation and function of OC, promotes the production of osteogenic factors in OC lineage cells, and leads to increased bone formation in women		(33, 110)
	Inflammation	PGRN significantly decreased the mRNA and protein levels of TNF-α and IL-1β.	It can inhibit ECM damage, inflammatory reaction of periodontal tissue, reduce inflammatory infiltration, and alleviate the progress of periodontitis	CP	(115)
	OB differentiation	PGRN increased BV/TV, Tb, ALP and Runx2 expression, decreased SP. PGRN at appropriate concentration promoted the proliferation of PDLSCs, increased the expression of ALP and Runx2 mRNA, decreased the expression of TNF-α, and promoted the differentiation of OB.	Increased the area of new bone and improved the quality of bone.		(116, 117)
	Inflammation- Bone coupling	PGRN depended on TNFR2, increased the expression of p-ERK1/2, p-JNK, ALP and Runx2, decreased the expression of TNF-α and the number of TRAP positive cells, and inhibited the formation of OC. PGRN inhibited the expression of TNF-α, NF-κB and p65 depending on TNFR1, and finally inhibited TNF-α/TNFR1/NF-κB pathway and activated ERK, TNFR2/JNK pathway	Reduces periodontal inflammation and promotes OB differentiation		(116, 119)