Blocking a sclerostin-fat cell interaction may restore lipid and glucose balance in mice

Osteoporosis and type 2 diabetes (T2DM) often coexist in postmenopausal women. Sclerostin, a protein that suppresses bone formation, also appears to impair whole-body lipid and glucose metabolism. The approved antibody romosozumab, which mainly targets sclerostin's loop2, builds bone and improves metabolism in mice, but regulators have warned of cardiovascular risk. A drug that keeps the benefits without that risk would be valuable.

The team first looked at human and mouse data. In a roughly 5-year community follow-up, serum sclerostin rose in 119 people after they were newly diagnosed with T2DM compared with their own baselines. Among postmenopausal osteoporosis patients, those with T2DM (n=24) had higher sclerostin, free fatty acids, triglycerides, HbA1c and fasting glucose than those without (n=22). Ovariectomized mice fed a high-fat diet (HFD) likewise had higher sclerostin and worse metabolic measures.

They then tested sclerostin's loop3, a region their earlier work linked to bone suppression but not to sclerostin's cardioprotective effect. Mice carrying full-length human sclerostin had larger fat pads and adipocytes, higher free fatty acids, higher fasting glucose and poorer glucose tolerance and insulin sensitivity than wild-type mice. Mice with loop3 deleted were improved on these measures. Treating sclerostin-knock-in mice for 12 weeks with Apc001OA, a half-life-extended loop3-specific aptamer, reduced fat pad weight and adipocyte size and improved glucose handling, with shifts in IRS1/AKT phosphorylation in fat tissue.

In HFD-fed mice, a loop3 mutation lowered fat mass and free fatty acids and improved glucose handling without changing body weight or food intake, while also increasing trabecular and cortical bone and bone strength. In a therapeutic study, 8 weeks of Apc001OA lowered body weight, gWAT weight, free fatty acids and adipocyte size and improved glucose and insulin tolerance, comparable in many respects to semaglutide as a positive control. Apc001OA did not change food intake. Mechanistically, protein interaction assays identified LRP4 as a loop3 receptor in adipocytes, and per the abstract, specifically blocking the adipocytic loop3-LRP4 interaction attenuated sclerostin's metabolic impairment in vitro and in vivo (the supplied text is truncated before these experiments).

The findings suggest a precision strategy: inhibiting loop3-LRP4 signalling might treat bone loss and metabolic disease together while avoiding the cardiovascular concern. Caveats are important: the work is largely in mice, human data are small and associative, gene-expression changes were sometimes inconsistent between models (for example, lipid-gene expression fell in knock-in mice but rose in HFD mice), and cardiovascular safety in humans remains untested.