Neutralization of oxidized phospholipids attenuates age‐associated bone loss in mice

Abstract

Oxidized phospholipids (OxPLs) are pro‐inflammatory molecules that affect bone remodeling under physiological conditions. Transgenic expression of a single‐chain variable fragment (scFv) of the antigen‐binding domain of E06, an IgM natural antibody that recognizes the phosphocholine (PC) moiety of OxPLs, increases trabecular and cortical bone in adult male and female mice by increasing bone formation. OxPLs increase with age, while natural antibodies decrease. Age‐related bone loss is associated with increased oxidative stress and lipid peroxidation and is characterized by a decline in osteoblast number and bone formation, raising the possibility that increased OxPLs, together with the decline of natural antibodies, contribute to age‐related bone loss. We show here that transgenic expression of E06‐scFv attenuated the age‐associated loss of spinal, femoral, and total bone mineral density in both female and male mice aged up to 22 and 24 months, respectively. E06‐scFv attenuated the age‐associated decline in trabecular bone, but not cortical bone, and this effect was associated with an increase in osteoblasts and a decrease in osteoclasts. Furthermore, RNA‐seq analysis showed that E06‐scFv increased Wnt10b expression in vertebral bone in aged mice, indicating that blocking OxPLs increases Wnt signaling. Unlike age‐related bone loss, E06‐scFv did not attenuate the bone loss caused by estrogen deficiency or unloading in adult mice. These results demonstrate that OxPLs contribute to age‐associated bone loss. Neutralization of OxPLs, therefore, is a promising therapeutic target for senile osteoporosis, as well as atherosclerosis and non‐alcoholic steatohepatitis (NASH), two other conditions shown to be attenuated by E06‐scFv in mice.

The role of WNT10B in physiology and disease: A 10-year update

“…WNT10B is considered a master negative regulator of adipocyte differentiation (see Section 8 ). Thus, WNT10B is often used as a marker of increased osteoblastogenesis, decreased adipogenesis, or both ( Liu et al, 2016 ; Matsushita et al, 2016 ; Yi et al, 2019 ; Palmieri et al, 2021 ), for example in bone marrow adipocytes ( Georgiou et al, 2015 ; Lee et al, 2019 ).…”

Lipids as Regulators of Cellular Senescence

“…Inhibition of TLR2 with oxid ized-1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (OxPAPC), a well-studied oxidized product of a common phospholipid in mammalian cell membranes, 1-palmitoyl-2-arachidonoyl-sn-phosphatidylcholine (PAPC) significantly reduced IL-1α and IL-1β mRNA induction in oncogene induced senescence of IMR90 cells. In another study targeting OxPLs by transgenic overexpressing of E06-svFv, a single chain variable fragment that binds to phosphatidyl choline head group of OxPL attenuated age-associated trabecular bone loss in both female and male mice ( Palmieri et al, 2021 ). Similar E06-svFv transgene mechanisms to inactivate OxPLs have been studied with age-associated diseases such as atheroscleosis, steatohepatitis ( Sun et al, 2020 ) and macular degeneration ( Handa et al, 2015 ) suggesting neutralizing OxPLs as a promising therapeutic target for some of the age-associated diseases.…”

Deletion of the scavenger receptor Scarb1 in osteoblast progenitors does not affect bone mass

“…Scarb1 is the most abundant scevenger receptor in osteoblasts that is known to bind PC-OxPL, which has deleterious effects on bone homeostasis mainly by affecting osteoblasts [10,15]. Male and female mice expressing an antibody fragment (E06-scFv) that neutralizes PC-OxPL, exhibit increased cancellous and cortical bone mass at 6 months of age [15] and are protected from the deleterious effect of aging on bone [16]. E06-scFV increases osteoblast number and activity and decreases osteoblast apopostosis, indicating that PC-OxPL affects osteoblasts under physiological conditions [15].…”

“…We have previously shown that physiological levels of PC-OxPL reduce bone mass. Specifically, we found that male and females transgenic mice expressing a single chain (scFv) form of the antigen-binding domain of E06 IgM (E06-scFv), which binds and neutralizes PC-OxPL, have increased trabecular and cortical bone mass at 6 months of age [14,15] and are protected from the bone loss caused by a high fat diet or aging [14,16]. The increase in bone mass in these mice is due mainly to an increase in osteoblast number and bone formation [14,15].…”