PTH/PTHrP Receptor Mediates Cachexia in Models of Kidney Failure and Cancer

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2015 Dec 17

PMID 26669699

Citations 148

Authors

Serkan Kir

Hirotaka Komaba

Ana P Garcia

Konstantinos P Economopoulos

Wei Liu

Beate Lanske

Richard A Hodin

Bruce M Spiegelman

Affiliations

Soon will be listed here.

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.

Citing Articles

Combating chronic kidney disease-associated cachexia: A literature review of recent therapeutic approaches.

Rahbar Saadat Y, Abbasi A, Hejazian S, Hekmatshoar Y, Ardalan M, Farnood F BMC Nephrol. 2025; 26(1):133.

PMID: 40069669 PMC: 11895341. DOI: 10.1186/s12882-025-04057-8.

Sarcopenia in Chronic Kidney Disease: A Narrative Review from Pathophysiology to Therapeutic Approaches.

Tsai C, Wang P, Hsiung T, Fan Y, Wu J, Kan W Biomedicines. 2025; 13(2).

PMID: 40002765 PMC: 11852367. DOI: 10.3390/biomedicines13020352.

Parathyroid hormone-related protein levels and treatment outcomes in hypercalcemia of malignancy: a retrospective cohort study.

Kato K, Nakashima A, Kimura A, Maruyama Y, Ohkido I, Miyazaki Y JBMR Plus. 2025; 9(3):ziae178.

PMID: 39925622 PMC: 11807284. DOI: 10.1093/jbmrpl/ziae178.

PTHrP Promotes RBP4 Expression Under the Control of PPARγ in the Kidney.

Nieto-Bona M, Carrasco A, Medina-Gomez G, Bosch R, Izquierdo-Lahuerta A Int J Mol Sci. 2025; 26(1.

PMID: 39795999 PMC: 11719952. DOI: 10.3390/ijms26010142.

Characteristics of lipid metabolism and fat distribution in patients with primary hyperparathyroidism and their Mendelian randomization study.

Zhang Y, Yang M, Wu Y, Wang Q Endocrine. 2024; .

PMID: 39702647 DOI: 10.1007/s12020-024-04141-3.

References

Iguchi H, Onuma E, Sato K, Ogata E . Involvement of parathyroid hormone-related protein in experimental cachexia induced by a human lung cancer-derived cell line established from a bone metastasis specimen. Int J Cancer. 2001; 94(1):24-7. DOI: 10.1002/ijc.1425. View

Kobayashi T, Chung U, Schipani E, Starbuck M, Karsenty G, Katagiri T . PTHrP and Indian hedgehog control differentiation of growth plate chondrocytes at multiple steps. Development. 2002; 129(12):2977-86. DOI: 10.1242/dev.129.12.2977. View

Jackson A, Shrikrishna D, Kelly J, Kemp S, Hart N, Moxham J . Vitamin D and skeletal muscle strength and endurance in COPD. Eur Respir J. 2012; 41(2):309-16. DOI: 10.1183/09031936.00043112. View

Shellock F, Riedinger M, Fishbein M . Brown adipose tissue in cancer patients: possible cause of cancer-induced cachexia. J Cancer Res Clin Oncol. 1986; 111(1):82-5. DOI: 10.1007/BF00402783. View

Tentori F, Wang M, Bieber B, Karaboyas A, Li Y, Jacobson S . Recent changes in therapeutic approaches and association with outcomes among patients with secondary hyperparathyroidism on chronic hemodialysis: the DOPPS study. Clin J Am Soc Nephrol. 2014; 10(1):98-109. PMC: 4284424. DOI: 10.2215/CJN.12941213. View

Peirce V, Carobbio S, Vidal-Puig A . The different shades of fat. Nature. 2014; 510(7503):76-83. DOI: 10.1038/nature13477. View

Tsoli M, Moore M, Burg D, Painter A, Taylor R, Lockie S . Activation of thermogenesis in brown adipose tissue and dysregulated lipid metabolism associated with cancer cachexia in mice. Cancer Res. 2012; 72(17):4372-82. DOI: 10.1158/0008-5472.CAN-11-3536. View

Neyra R, Chen K, Sun M, Shyr Y, Hakim R, Ikizler T . Increased resting energy expenditure in patients with end-stage renal disease. JPEN J Parenter Enteral Nutr. 2003; 27(1):36-42. DOI: 10.1177/014860710302700136. View

Cypess A, White A, Vernochet C, Schulz T, Xue R, Sass C . Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med. 2013; 19(5):635-9. PMC: 3650129. DOI: 10.1038/nm.3112. View

10.

Wu J, Bostrom P, Sparks L, Ye L, Choi J, Giang A . Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012; 150(2):366-76. PMC: 3402601. DOI: 10.1016/j.cell.2012.05.016. View

11.

DeBoer M . Animal models of anorexia and cachexia. Expert Opin Drug Discov. 2010; 4(11):1145-1155. PMC: 2771941. DOI: 10.1517/17460440903300842. View

12.

Penna F, Minero V, Costamagna D, Bonelli G, Baccino F, Costelli P . Anti-cytokine strategies for the treatment of cancer-related anorexia and cachexia. Expert Opin Biol Ther. 2010; 10(8):1241-50. DOI: 10.1517/14712598.2010.503773. View

13.

Yee-Moon Wang A, Sea M, Tang N, Sanderson J, Lui S, Kam-Tao Li P . Resting energy expenditure and subsequent mortality risk in peritoneal dialysis patients. J Am Soc Nephrol. 2004; 15(12):3134-43. DOI: 10.1097/01.ASN.0000144206.29951.B2. View

14.

Fearon K, Arends J, Baracos V . Understanding the mechanisms and treatment options in cancer cachexia. Nat Rev Clin Oncol. 2012; 10(2):90-9. DOI: 10.1038/nrclinonc.2012.209. View

15.

Vilardaga J, Romero G, Friedman P, Gardella T . Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm. Cell Mol Life Sci. 2010; 68(1):1-13. PMC: 3568769. DOI: 10.1007/s00018-010-0465-9. View

16.

Kir S, White J, Kleiner S, Kazak L, Cohen P, Baracos V . Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature. 2014; 513(7516):100-4. PMC: 4224962. DOI: 10.1038/nature13528. View

17.

Roe S, Cooper A, Morris I, Rothwell N . Mechanisms of cachexia induced by T-cell leukemia in the rat. Metabolism. 1996; 45(5):645-51. DOI: 10.1016/s0026-0495(96)90037-2. View

18.

Cheung W, Ding W, Gunta S, Gu Y, Tabakman R, Klapper L . A pegylated leptin antagonist ameliorates CKD-associated cachexia in mice. J Am Soc Nephrol. 2013; 25(1):119-28. PMC: 3871780. DOI: 10.1681/ASN.2013040432. View

19.

Cabe P, Tilson H, Mitchell C, Dennis R . A simple recording grip strength device. Pharmacol Biochem Behav. 1978; 8(1):101-2. DOI: 10.1016/0091-3057(78)90131-4. View

20.

Childs K, Welz T, Samarawickrama A, Post F . Effects of vitamin D deficiency and combination antiretroviral therapy on bone in HIV-positive patients. AIDS. 2011; 26(3):253-62. DOI: 10.1097/QAD.0b013e32834f324b. View