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ENPP1 deletion causes mouse osteoporosis via the MKK3/p38 MAPK/PCNA signaling pathway
Qiang Wang1, Zhiqiang Gao1, Kai Guo1
1Department of Spine Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd., Shanghai, 200120, China.
Background:
Apart from the current understanding of enzyme function, the mechanism of ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) deficiency-associated osteoporosis is unknown. We aimed to explore the changes in the expression of signaling pathways of bone tissues involved in Enpp1 deficiency.
Methods:
The body weights and morphology and histology of the bones of male Enpp1 knockout (KO) and wild-type (WT) mice were assessed. The humeri of WT and Enpp1 KO mice at 12 weeks of age were subjected to high-throughput quantitative molecular measurements, and bioinformatics analysis was performed. Proteins from humeri and calvarial pre-osteoblasts (Pobs) were used to verify the differentially expressed signaling pathways and to explain the mechanism of Enpp1 deficiency-associated osteoporosis.
Results:
Enpp1 KO mice had significantly lower body weight and trabecular bone mass in the hindlimbs than WT mice. Proteomics and immunoblotting showed that Enpp1 deletion downregulated the expression of the p38 mitogen-activated protein kinase (MAPK) signaling pathway in bones. Lysophosphatidic acid (LPA) was involved in activating the MKK3/p38 MAPK/PCNA pathway and proliferating Pobs in Enpp1 KO mice, whereas a p38 MAPK inhibitor suppressed the LPA-induced pro-proliferation phenotype (p < 0.05).
Conclusion:
The inhibition of MKK3/p38 MAPK/PCNA pathway plays an important role in the development of osteoporosis caused by Enpp1 deficiency, and LPA partially rescued the proliferation of pre-osteoblasts via the MKK3/p38 MAPK/PCNA pathway.
Insights
Ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) deficiency leads to osteoporosis by inhibiting the MKK3/p38 MAPK/PCNA pathway. Lysophosphatidic acid (LPA) partially restores pre-osteoblast proliferation in Enpp1 knockout mice.
Area of Science:
- Bone Biology
- Molecular Mechanisms of Disease
- Enzyme Function and Regulation
Background:
- The mechanism underlying osteoporosis in ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) deficiency remains unclear.
- This study investigates alterations in bone tissue signaling pathways associated with Enpp1 deficiency.
Purpose of the Study:
- To elucidate the molecular mechanisms of Enpp1 deficiency-induced osteoporosis.
- To identify key signaling pathways affected by Enpp1 deficiency in bone.
Main Methods:
- Comparative analysis of Enpp1 knockout (KO) and wild-type (WT) mice, including body weight, bone morphology, and histology.
- High-throughput quantitative molecular measurements and bioinformatics analysis of humeri from WT and Enpp1 KO mice.
- Proteomic and immunoblotting analyses of bone and pre-osteoblast proteins to verify differentially expressed pathways.
Main Results:
- Enpp1 KO mice exhibited reduced body weight and trabecular bone mass compared to WT mice.
- Enpp1 deletion downregulated the p38 mitogen-activated protein kinase (MAPK) signaling pathway in bone tissues.
- Lysophosphatidic acid (LPA) activated the MKK3/p38 MAPK/PCNA pathway, promoting pre-osteoblast proliferation in Enpp1 KO mice, an effect suppressed by a p38 MAPK inhibitor.
Conclusions:
- Inhibition of the MKK3/p38 MAPK/PCNA pathway is crucial in the pathogenesis of Enpp1 deficiency-associated osteoporosis.
- LPA partially rescues pre-osteoblast proliferation through the MKK3/p38 MAPK/PCNA pathway in the context of Enpp1 deficiency.
