mTOR Inhibition Subdues Milk Disorder Caused by Maternal VLDLR Loss

Publication date: 6 June 2017
Source:Cell Reports, Volume 19, Issue 10
Author(s): HoangDinh Huynh, Wei Wei, Yihong Wan
It is unknown whether and how very-low density lipoprotein receptors (VLDLRs) impact skeletal homeostasis. Here, we report that maternal and offspring VLDLRs play opposite roles in osteoclastogenesis and bone resorption. VLDLR deletion in the offspring augments osteoclast differentiation by enhancing RANKL signaling, leading to osteoporosis. In contrast, VLDLR deletion in the mother alters milk metabolism, which inhibits osteoclast differentiation and causes osteopetrosis in the offspring. The maternal effects are dominant. VLDLR-null lactating mammary gland exhibits higher mTORC1 signaling and cholesterol biosynthesis. Pharmacological probing reveals that rapamycin, but not statin, treatment of the VLDLR-null mother can prevent both the low bone resorption and our previously described inflammatory fur loss in their offspring. Genetic rescue reveals that maternal mTORC1 attenuation in adipocytes, but not in myeloid cells, prevents offspring osteopetrosis and fur loss. Our studies uncover functions of VLDLR and mTORC1 in lactation and osteoclastogenesis, illuminating key mechanisms and therapeutic insights for bone and metabolic diseases.

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Teaser

Huynh et al. report that osteoclastogenesis and bone resorption are enhanced by offspring VLDLR deletion due to augmented RANKL signaling but impaired by maternal VLDLR deletion due to excessive mTOR signaling in the lactating mammary gland, providing key insights for VLDLR functions, milk metabolism, and maternal regulation of offspring traits.


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