TABLE 2.

The effects of different DKK1 inhibitors in multiple models.

DKK1 inhibitors		Regulatory activities	References
Small molecules	NCI8642	NCI8642 reversed the DKK1-mediated inhibition of Wnt signaling, but its effect was concentration-dependent	Iozzi et al. (2012)
Biomacromolecules	BHQ880	In the SCID-hu murine model, BHQ880 inhibited the growth of MM cells in the presence of BMSCs in vitro, and it also showed anti-osteolytic effects in the 5T2MM murine model of myeloma. In addition, BHQ880 could activate the Wnt pathway, attenuate metastasis, promote differentiation, and slow tumor growth in an orthotopic implantation/amputation model of osteosarcoma metastasis	Fulciniti et al. (2009), Heath et al. (2009), Goldstein et al. (2016)
	DKN-01	DKN-01 showed indirect anti-MM effects in preclinical studies and phase I testing, and DKN-01 treatment prolonged the median OS in patients with advanced NSCLC	Pozzi et al. (2013), Edenfield et al. (2014)
	RH2-18	RH2-18 could restore Wnt-induced activities, and BMD was increased in ovariectomized mice and rhesus macaques	Glantschnig et al. (2010); Glantschnig et al. (2011)
	Hetero-DS	Hetero-DS promoted bone mass accrual and fracture repair, and it showed more robust therapeutic efficacy than parental antibodies (Scl-Ab and DKK1-Ab)	Heiland et al. (2010), Florio et al. (2016)
	Cyclized Oligopeptide	An oligopeptide showed bone-anabolic effects in vitro and significantly reduced the tumor burden in the MOPC315.BM.Luc MM mouse model	Park et al. (2017)
Nucleic acids	Anti-sense oligonucleotides	Several anti-sense oligonucleotides have been used to inhibit DKK1 expression in vivo, and loss of bone mass was abrogated in ovariectomized rats after treatment	Wang et al. (2007), Weng et al. (2010), Weng et al. (2012)
	SiRNAs	Transfection of DKK1-siRNA into cells and mice could attenuate DKK1 expression, thereby stimulating osteoblast differentiation or decreasing abnormal cell proliferation in different models	Butler et al. (2010); Feng et al. (2019)
	MiRNAs	MiRNAs inhibit DKK1 expression by directly binding to the 3′-UTR of DKK1 mRNA and have been applied in various cancer models	Zovoilis et al. (2009), Jiang et al. (2017), Wang et al. (2018c)
	DKK1 vaccines	DKK1 vaccines helped to elicit immune responses to alleviate myeloma in the murine MOPC-21 myeloma model, with remarkable therapeutic efficacy in tumor inhibition experiments. Furthermore, a multiepitope DKK1 vaccine could attenuate bone erosion and lower the disease incidence of arthritis in CIA mice	Qian and Yi (2012); Zhang et al. (2015a)