Osteoclasts are multinucleated cells essential for bone-resorption. Successful repair
of bone defciencies still remains a great challenge worldwide. The signaling factor
angiopoietin-like protein 2 (ANGPTL2), one of eight ANGPTL proteins, functions in
maintenance of tissue homeostasis partly through regulating inflammation. In the study,
ANGPTL2 expression was promoted during osteoclast development and that suppressing
ANGPTL2 alleviated osteoclast production regulated by macrophage colony-stimulating
factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). The results suggested
that ANGPTL2 knockdown inhibited M-CSF-caused proliferation of osteoclast precursor
cells. Further, ANGPTL2 silence reduced nuclear factor of activated T cell c 1 (NFATC1)
and NFATC4 expressions in M-CSF-treated cells, along with decreased Runx2, OPN and
Colla1. Moreover, silencing ANGPTL2 down-regulated M-CSF-promoted expressions of pro-inflammatory
cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and
chemoattractant protein-1 (CCL-2). Consistently, ANGPTL2 knockdown reduced M-CSF-enhanced
activation of IKKα, IκBα and nuclear factor κB (NF-κB) and mitogen-activated protein
kinases (MAPKs) (p38 MAPK, ERK1/2 MAPK and JNK MAPK). Additionally, knockdown of ANGPTL2
inhibited the induction of Cyclin D1, Cyclin D2 and Cyclin E1 due to M-CSF exposure.
In vivo, we confirmed that ANGPTL2 knockout (KO) mice were protected against osteoporosis
induced by ovariectomy (OVX), as proved by the improved bone loss and bone mineral
density (BMD). Decreased expression of NFATCs was also observed in OVX-induced mice
in the absence of ANGPTL2. Elevated release of pro-inflammatory cytokines was abrogated
by ANGPTL2 knockout in femoral heads of mice with OVX operation, accompanied with
a significant reduction of phosphorylated NF-κB and MAPKs signaling pathways. And
down-regulated expression of Cyclin D1, Cyclin D2 and Cyclin E1 was observed in OVX-operated
mice with ANGPTL2 knockout. Therefore, our study indicated that ANGPTL2 played an
essential role in osteoclast generation through regulating the proliferation and inflammation
of osteoclast lineage cells, providing new insights into the therapeutic strategy
to alleviate bone loss.