In conclusion, our findings suggested that Enpp1 deficiency-associated osteoporosis involves inhibition of the MKK3/p38 MAPK/PCNA signaling pathway and that LPA partially rescued the impacted proliferation of pre-osteoblasts via the MKK3/p38 MAPK/PCNA pathway, which deepened our understanding of the mechanism of early-onset osteoporosis caused by deletion mutation of Enpp1 gene and provides some help for clinical treatment. The gene discussed is ENPP1; the disease is osteoporosis.