title: PTH/PTHrP Receptor Mediates Cachexia in Models of Kidney Failure and Cancer.
abstract: Cachexia is a wasting syndrome associated with elevated basal energy expenditure and loss of adipose and muscle tissues. It accompanies many chronic diseases including renal failure and cancer and is an important risk factor for mortality. Our recent work demonstrated that tumor-derived PTHrP drives adipose tissue browning and cachexia. Here, we show that PTH is involved in stimulating a thermogenic gene program in 5/6 nephrectomized mice that suffer from cachexia. Fat-specific knockout of PTHR blocked adipose browning and wasting. Surprisingly, loss of PTHR in fat tissue also preserved muscle mass and improved muscle strength. Similarly, PTHR knockout mice were resistant to cachexia driven by tumors. Our results demonstrate that PTHrP and PTH mediate wasting through a common mechanism involving PTHR, and there exists an unexpected crosstalk mechanism between wasting of fat tissue and skeletal muscle. Targeting the PTH/PTHrP pathway may have therapeutic uses in humans with cachexia.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Serkan
authors.initials: S
authors.lastname: Kir
authors.affiliation: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Komaba
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Garcia
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Konstantinos P
authors.initials: KP
authors.lastname: Economopoulos
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Beate
authors.initials: B
authors.lastname: Lanske
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Hodin
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: bruce_spiegelman@dfci.harvard.edu.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001284:Atrophy; D002100:Cachexia / Q000150:complications* / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000150:complications* / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006961:Hyperparathyroidism / Q000150:complications / Q000235:genetics; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology; D009392:Nephrectomy; D010281:Parathyroid Hormone / Q000378:metabolism* / Q000494:pharmacology; D044162:Parathyroid Hormone-Related Protein / Q000494:pharmacology; D051381:Rats; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism*; D051437:Renal Insufficiency / Q000150:complications* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D022722:Thermogenesis / Q000187:drug effects / Q000235:genetics; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D044168:Receptor, Parathyroid Hormone, Type 1; D000071256:Uncoupling Protein 1
keywords: PTHrP; adipose tissue browning; cachexia; cancer; chronic kidney disease; parathyroid hormone (PTH); skeletal muscle atrophy