mTOR Inhibition Subdues Milk Disorder Caused by Maternal VLDLR Loss

Hoang Dinh Huynh, Wei Wei, Yihong Wan

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2014-2025
Number of pages12
JournalCell Reports
Volume19
Issue number10
DOIs
StatePublished - Jun 6 2017

Fingerprint

Milk
Mothers
Osteopetrosis
Bone
Osteoclasts
Bone Resorption
Osteogenesis
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Metabolic Bone Diseases
Biosynthesis
Myeloid Cells
Sirolimus
Human Mammary Glands
VLDL receptor
Lactation
Adipocytes
Metabolism
Osteoporosis
Homeostasis
Cholesterol

Keywords

  • bone resorption
  • cholesterol
  • hair
  • inflammation
  • lactation
  • maternal
  • milk
  • mTOR
  • osteoclast
  • VLDLR

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

mTOR Inhibition Subdues Milk Disorder Caused by Maternal VLDLR Loss. / Huynh, Hoang Dinh; Wei, Wei; Wan, Yihong.

In: Cell Reports, Vol. 19, No. 10, 06.06.2017, p. 2014-2025.

Research output: Contribution to journalArticle

Huynh, Hoang Dinh ; Wei, Wei ; Wan, Yihong. / mTOR Inhibition Subdues Milk Disorder Caused by Maternal VLDLR Loss. In: Cell Reports. 2017 ; Vol. 19, No. 10. pp. 2014-2025.
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