Endogenous parathyroid hormone-related protein compensates for the absence of parathyroid hormone in promoting bone accrual in vivo in a model of bone marrow ablation

AbstractCancer cachexia is a metabolic disorder characterized by skeletal muscle wasting and white adipose tissue browning. Specific functions of several hormones, growth factors, and cytokines derived from tumors can trigger cachexia. Moreover, adipose tissue lipolysis might explain weight loss that occurs owing to cachexia. Extracellular vesicles (EVs) are involved in intercellular communication. However, whether EVs participate in lipolysis induced by cancer cachexia has not been thoroughly investigated. Using Lewis lung carcinoma (LLC) cell culture, we tested whether LLC cell-derived EVs can induce lipolysis in 3T3-L1 adipocytes. EVs derived from LLC cells were isolated and characterized biochemically and biophysically. Western blotting and glycerol assay were used to study lipolysis. LLC cell-derived EVs induced lipolysis in vivo and vitro. EVs fused directly with target 3T3-L1 adipocytes and transferred parathyroid hormone-related protein (PTHrP), activating the PKA signaling pathway in 3T3-L1 adipocytes. Blocking PTHrP activity in LLC-EVs using a neutralizing antibody and by knocking down PTHR expression prevented lipolysis in adipocytes. Inhibiting the PKA signaling pathway also prevents the lipolytic effects of EVs. In vivo, suppression of LLC-EVs release by knocking down Rab27A alleviated white adipose tissue browning and lipolysis. Our data showed that LLC cell-derived EVs induced adipocyte lipolysis via the extracellular PTHrP-mediated PKA pathway. Our data demonstrate that LLC-EVs induce lipolysis in vitro and vivo by delivering PTHrP, which interacts with PTHR. The lipolytic effect of LLC-EVs was abrogated by PTHR knockdown and treatment with a neutralizing anti-PTHrP antibody. Together, these data show that LLC-EV-induced lipolysis is mediated by extracellular PTHrP. These findings suggest a novel mechanism of lipid droplet loss and identify a potential therapeutic strategy for cancer cachexia.

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High-Affinity HLA-A(*)02.01 Peptides from Parathyroid Hormone-Related Protein Generate In Vitro and In Vivo Antitumor CTL Response Without Autoimmune Side Effects

The Journal of Immunology ◽

10.4049/jimmunol.169.9.4840 ◽

2002 ◽

Vol 169 (9) ◽

pp. 4840-4849 ◽

Cited By ~ 27

Author(s):

Guido Francini ◽

Antonio Scardino ◽

Kostas Kosmatopoulos ◽

François A. Lemonnier ◽

Giuseppe Campoccia ◽

...

Keyword(s):

Parathyroid Hormone ◽

Side Effects ◽

Related Protein ◽

Ctl Response ◽

High Affinity ◽

Parathyroid Hormone Related Protein

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Parathyroid hormone-related protein (PTHrP)-(1-139) isoform is efficiently secreted in vitro and enhances breast cancer metastasis to bone in vivo

Bone ◽

10.1016/s8756-3282(02)00685-3 ◽

2002 ◽

Vol 30 (5) ◽

pp. 670-676 ◽

Cited By ~ 64

Author(s):

T.A Guise ◽

J.J Yin ◽

R.J Thomas ◽

M Dallas ◽

Y Cui ◽

...

Keyword(s):

Breast Cancer ◽

Parathyroid Hormone ◽

Cancer Metastasis ◽

Breast Cancer Metastasis ◽

Related Protein ◽

Parathyroid Hormone Related Protein

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The synthetic human parathyroid hormone-related protein is inhibited by a parathyroid hormone antagonist in rats in vivo

Journal of Bone and Mineral Research ◽

10.1002/jbmr.5650050603 ◽

2009 ◽

Vol 5 (6) ◽

pp. 541-545 ◽

Cited By ~ 6

Author(s):

Noboru Horiuchi ◽

Takashi Hongo ◽

Thomas L. Clemens

Keyword(s):

Parathyroid Hormone ◽

Related Protein ◽

Human Parathyroid Hormone ◽

Parathyroid Hormone Related Protein

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The Association of Parathyroid Hormone Related Protein and Vitamin D Level with Serum Calcium Ion in Acute Leukemia Patients

INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY ◽

10.24293/ijcpml.v26i3.1554 ◽

2020 ◽

Vol 26 (3) ◽

Author(s):

Niniek Wiendayanthi ◽

MI. Diah Pramudianti ◽

Yuwono Hadisuparto

Keyword(s):

Bone Marrow ◽

Vitamin D ◽

Parathyroid Hormone ◽

Acute Leukemia ◽

Serum Calcium ◽

Calcium Ion ◽

Receiver Operating Curve ◽

Related Protein ◽

Parathyroid Hormone Related Protein ◽

D 20

Acute leukemia is bone marrow clonal cell malignancy. One of its complications is hypercalcemia. Parathyroid Hormone-Related Protein (PTHrP) activities involve the regulation of Calcium (Ca) metabolism. Vitamin D is a steroid involved in Ca homeostasis and bone mineralization. This study aimed to analyze PTHrP and vitamin D levels with serum calcium ion in acute leukemia. A cross-sectional study was performed in Clinical Pathology Dr. Moewardi General Hospital Surakarta between July and August 2019, consisting of 41 subjects with new acute leukemia who were diagnosed based on bone marrow puncture and or immunophenotyping result. The cut-off value of Ca ion serum and PTHrP level were determined with a Receiver Operating Curve (ROC). The data were analyzed with a 2x2 table, followed by multivariate logistic regression analysis, and p<0.05 was considered significant. Statistical analysis showed the median age of 25 (2-68) years, 23 (56.10%) ALL, and 18 (43.90%) non-ALL patients. The median of Ca ion and PTHrP were 1.08 (0.84-1.21) mmol/l and 307.52 (20.77-1104.26) pg/mL, respectively. The mean level of vitamin D was 26.45±11.40 ng/mL. Bivariate analysis showed that PTHrP levels ≥ 110.09 pg/mL and vitamin D ≥ 20 ng/mL were related to serum Ca ion ≥ 1.07 mmol/l (PR 4.675; 95% CI: 1.211-18.041; p=0.021 and PR 5.143; 95% CI: 1.279-20.677; p=0.017). Multivariate analysis showed that PTHrP ≥ 110.09 pg/mL and vitamin D ≥ 20 ng/mL were associated with serum Ca ion ≥1.07 mmol/l. There was a significant association between PTHrP, vitamin D level, and serum Ca ion in acute leukemia patients.

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