Low-density lipoprotein receptor deficiency reduced bone mass in mice via the c-fos/NFATc1 pathway

The low-density lipoprotein receptor (LDLR) plays a crucial role in regulating lipid metabolism. However, whether LDLR deficiency affects bone mass and morphology remains controversial. This study aimed to analyze the bone phenotypes of LDLR knockout (LDLR^-/-) mice.

Eight-week-old LDLR^-/- and wild-type (WT) mice were subjected to microcomputed tomography to detect bone phenotypes. Enzyme-linked immunosorbent assay kits were used to detect the serum estrogen levels and matrix metalloproteinase 9 (MMP-9) levels in tissue homogenates. Von Kossa, toluidine blue, tartrate-resistant acid phosphatase (TRAP) staining, and calcein labeling were performed to explore bone turnover parameters. In vitro, osteoclastogenesis was induced in bone marrow cells from LDLR^-/- mice and WT mice in the presence or absence of 17β-estradiol. The microphotographs and number of osteoclasts were validated using TRAP staining. Relative gene expression during osteoclast differentiation and maturation was determined by quantitative real-time polymerase chain reaction.

LDLR deficiency results in reduced bone mineral density of the tibial cancellous bone, indicating bone loss to some extent in LDLR^-/- mice. LDLR deficiency significantly increased the number of osteoclasts, but not osteoblasts. In vitro, bone marrow cells from LDLR^-/- mice displayed enhanced osteoclastic potential along with increased expression of TRAP, cathepsin K, nuclear factor of activated T-cells 1 (NFATc1), c-fos, and MMP-9 and inhibited dendritic cell-specific transmembrane protein expression. Moreover, 17β-estradiol treatment can inhibit osteoclastogenesis in vitro.

Our data demonstrated that LDLR deficiency promoted osteoclastogenesis by upregulating c-fos and NFATc1 expression, reducing cancellous bone mass in LDLR^-/- mice.