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Librizzi, M.; Naselli, F.; Abruscato, G.; Luparello, C.; Caradonna, F. PTHrP-Related Signatures in Adipogenesis and Transdifferentiation. Encyclopedia. Available online: https://encyclopedia.pub/entry/46638 (accessed on 17 June 2024).
Librizzi M, Naselli F, Abruscato G, Luparello C, Caradonna F. PTHrP-Related Signatures in Adipogenesis and Transdifferentiation. Encyclopedia. Available at: https://encyclopedia.pub/entry/46638. Accessed June 17, 2024.
Librizzi, Mariangela, Flores Naselli, Giulia Abruscato, Claudio Luparello, Fabio Caradonna. "PTHrP-Related Signatures in Adipogenesis and Transdifferentiation" Encyclopedia, https://encyclopedia.pub/entry/46638 (accessed June 17, 2024).
Librizzi, M., Naselli, F., Abruscato, G., Luparello, C., & Caradonna, F. (2023, July 11). PTHrP-Related Signatures in Adipogenesis and Transdifferentiation. In Encyclopedia. https://encyclopedia.pub/entry/46638
Librizzi, Mariangela, et al. "PTHrP-Related Signatures in Adipogenesis and Transdifferentiation." Encyclopedia. Web. 11 July, 2023.
PTHrP-Related Signatures in Adipogenesis and Transdifferentiation
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Parathyroid-hormone-related protein (PTHrP) is a protein hormone of 139, 141, or 173 amino acids, which may be cleaved into smaller bioactive forms, comprising amino terminus, mid-region, and carboxy terminus peptides, active as key controllers of viability, proliferation, and differentiation in diverse normal and pathological cell and tissue model systems via the reprogramming of gene expression and intracellular signalization.

cell biology gene expression adipose tissue

1. A Brief Note about Parathyroid Hormone-Related Protein (PTHrP) Structure and Function

PTHrP is the product of the PTHLH gene, which extends more than 15 kb of genomic DNA located on chromosome 12. The PTHLH gene exhibits a complex organization with three different promoters and alternative splicing mechanisms producing multiple mRNA variants which differentiate in their 3′ ends encompassing both coding and untranslated regions. Three isoforms of 139, 141, and 173 amino acids with distinct C-terminals are the protein products of the different translation patterns (Table 1). The extreme N-terminus displays sequence homology with PTH, thus binding with equal affinity to the shared G protein-linked PTH/PTHrP receptor PTH1R.
Table 1. Variants of PTHrP mRNA produced via alternative splicing at the 5′ and 3′ ends [1].
PTHrP isoforms are polyhormones subjected to different post-translational processing that generates smaller secretory forms of the peptide. These include PTHrP (1–36), which contains homology with PTH and activates PTH1R. Other peptides consist of the mid-region fragments, such as (38–94) and (67–86), which have been shown to influence transplacental calcium transport and the growth and invasive behavior of breast epithelial cells, and the C-terminal fragment comprising PTHrP (107–139), also known as osteostatin, which has been shown to act on skin, heart, and bone cells [2].
The presence of a lysine/arginine-rich bipartite sequence in the mid-region PTHrP fragment, which is homologous to the nuclear/nucleolar targeting signal (NTS) present in SV40 large tumor antigen (able to direct importin β/Ran GTPase-mediated import), may allow an “intracrine” route supplementing the autocrine/paracrine counterpart [3].
Over the past 30 years, a great deal of research has demonstrated that PTHrP participates in various complex signaling pathways through its membrane and nuclear effects. It has been shown that the full-length protein and its discrete fragments are multifaceted critical regulators of proliferation, differentiation, and apoptosis acting on PKA- or PKC-mediated signalization, whose main, but not exclusive, targets are P21, Akt, and NF-κB. A detailed molecular dissection of the involvement of PTHrP in signal transduction mechanisms has been the object of an extensive review literature [4][5]. On the other hand, PTHrP or its discrete domains have been proven to affect gene expression in a direct and substantial way in both normal, disease-affected, and neoplastic cells. A comprehensive recapitulation of PTHrP-dependent modulation of gene signatures in cancer cells has already appeared [6].

2. Adipose Tissue: PTHrP-Related Signatures in Adipogenesis and Transdifferentiation

Adipogenesis regulates adipose tissue expansion and function [7]. Despite the well-known role of PTHrP in the differentiation programming of stem cells into different cellular linages, its role in the regulation of adipogenic differentiation by human fat tissue-derived stem cells has only been partially elucidated at the gene expression level. Roca-Rodriguez et al. [8] showed that PTHrP was expressed in both visceral and subcutaneous adipose tissue in humans. Moreover, PTHRP expression progressively decreased during adipogenesis from undifferentiated mesenchymal cells. As a confirmation, data collected after PTHRP silencing in adipogenesis-committed stem cells demonstrated the downregulation of the adipogenic markers PPARG2, FABP4, ADRP, and CEBPA, coding for peroxisome proliferator activated receptor γ, fatty acid-binding protein 4, lipid droplet-associated adipose differentiation-related protein, and transcription factor CCAAT enhancer-binding protein α, respectively. Furthermore, they showed that PTHRP expression correlated with obesity-related morbidities, such as the setting of insulin resistance and the increase in body mass index and hip circumference in patients affected by type 2 diabetes, thereby defining PTHrP as a key regulator of their development. The mechanism via which PTHrP may switch the differentiation of stem cells from adipo- to osteogenesis, thereby inhibiting fat tissue formation, was studied in the rodent pluripotent mesenchymal cell line C3H10T1⁄2. Co-exposure of cells to bone morphogenetic protein-2 (BMP2) and PTHrP determined the downregulation of PPARγ and aP2 (adipocyte fatty acid-binding protein) and the concurrent upregulation of alkaline phosphatase, type I collagen, and osteocalcin mRNA levels. The PKC-mediated signalization was found to be at least in part implicated in this activity [9].
Dealing with bone-adipose tissue endocrine interplay, Zhang et al. [10] demonstrated that, in Ptch1c/c;HOC-Cre mutant mice, characterized by the perturbation of energy metabolism, the upregulated Hedgehog signalization increased bone-derived PTHrP release. This, in turn, triggered the modulation of the PKA/cAMP and Akt/Foxo pathways, leading to the overexpression of UCP1, coding for the uncoupling protein-1 that mediates energy expenditure via thermogenesis, with subsequent white adipose tissue (WAT) browning and enhancement of heat production. Moreover, PTHrP determined the increase of adiponectin mRNA and protein levels [10]. Adiponectin is involved in glucose homeostasis, because of its insulin-sensitizing activity [11][12], thereby indicating that PTHrP is also involved in the regulation of energy metabolism at this level. Since skeletal muscles also contribute to energy metabolism, it was also proven that in the mutant mice they underwent atrophy and adiponectin-triggered increase of fatty acid via significant upregulation of the genes whose products are involved in fatty acid oxidation (ACO, CPT1, and FABP3) and glucose uptake (GLUT1 and GLUT4). The action of adiponectin was mediated by the activation of 5′-AMP-activated protein kinase (AMPK); moreover, in the mutant mice AMPK was also activated in the liver in which the expression of GLUT1 was markedly increased. Therefore, in this experimental model, PTHrP, along with adiponectin’s contribution, was responsible for hypoglycemia due to glucose uptake and systemic fatty acid oxidation. As further support for this evidence, PTHrP was also found implicated in the higher rate of oxygen consumption and waste of fat and muscle tissues occurring in the Lewis lung carcinoma model of cancer cachexia developed in syngeneic C57BL/6 mice [13]. In particular, PTHrP (1–34), released among the tumor-derived factors, was proven to stimulate thermogenic gene expression, specifically upregulating UCP1 and DIO2, the latter coding for type 2 iodothyronine deiodinase, a selenoenzyme which increases during cold stress only in brown adipose tissue, ultimately resulting in the onset of hypermetabolism [14].
A recent study by Qin and colleagues [15] highlighted the role of PTHrP in both opposing brown adipose tissue (BAT) whitening and promoting WAT browning in mice transduced with adeno-associated PTHrP-encoding virus vector, submitted to a high-fat diet (HFD) for some weeks. PTHrP was found to protect the animals from the diet–induced onset of obesity stimulating WAT transdifferentiation and maintenance of BAT via upregulation of UCP1, UCP2, and PGC1α, the latter coding for PPARγ coactivator 1α. Moreover, VEGFA, coding for vascular endothelial growth factor A, was upregulated and considered responsible of the concomitant state of inflammation in BAT. In parallel, in the liver of HFD-submitted mice, overexpression of PTHrP was proven not only to attenuate the transcription level of the genes coding for enzymes and receptors responsible of fatty acid synthesis (ACSL1, FASN, and PPARG) but also to enhance that of lipolysis-related enzymes and receptors (ATGL, ACOX1, CPT1A, and PPARA). In addition, FGF21, coding for fibroblast growth factor 21, an atypical member of FGF family active on glucose and lipid metabolism [16] and on adiponectin production, was prominently upregulated in the liver of PTHrP-overexpressing mice, thereby resulting beneficial for the mitigation of the obesity-linked metabolic diseases such as hepatic steatosis, insulin resistance, and glucose intolerance.

References

  1. Longo, A.; Librizzi, M.; Naselli, F.; Caradonna, F.; Tobiasch, E.; Luparello, C. PTHrP in Differentiating Human Mesenchymal Stem Cells: Transcript Isoform Expression, Promoter Methylation, and Protein Accumulation. Biochimie 2013, 95, 1888–1896.
  2. Luparello, C. Parathyroid Hormone-Related Protein (PTHrP): A Key Regulator of Life/Death Decisions by Tumor Cells with Potential Clinical Applications. Cancers 2011, 3, 396–407.
  3. Martin, T.J.; Johnson, R.W. Multiple actions of parathyroid hormone-related protein in breast cancer bone metastasis. Br. J. Pharmacol. 2021, 178, 1923–1935.
  4. Martin, T.J. PTH1R Actions on Bone Using the cAMP/Protein Kinase A Pathway. Front Endocrinol. 2022, 12, 833221.
  5. Suva, L.J.; Friedman, P.A. Structural pharmacology of PTH and PTHrP. Vitam. Horm. 2022, 120, 1–21.
  6. Luparello, C.; Librizzi, M. Parathyroid hormone-related protein (PTHrP)-dependent modulation of gene expression signatures in cancer cells. Vitam. Horm. 2022, 120, 179–214.
  7. Lagathu, C.; Christodoulides, C.; Tan, C.Y.; Virtue, S.; Laudes, M.; Campbell, M.; Ishikawa, K.; Ortega, F.; Tinahones, F.J.; Fernández-Real, J.-M.; et al. Secreted Frizzled-Related Protein 1 Regulates Adipose Tissue Expansion and Is Dysregulated in Severe Obesity. Int. J. Obes. 2010, 34, 1695–1705.
  8. Roca-Rodríguez, M.M.; el Bekay, R.; Garrido-Sanchez, L.; Gómez-Serrano, M.; Coin-Aragüez, L.; Oliva-Olivera, W.; Lhamyani, S.; Clemente-Postigo, M.; García-Santos, E.; de Luna Diaz, R.; et al. Parathyroid Hormone-Related Protein, Human Adipose-Derived Stem Cells Adipogenic Capacity and Healthy Obesity. J. Clin. Endocrinol. Metab. 2015, 100, E826–E835.
  9. Chan, G.K.; Miao, D.; Deckelbaum, R.; Bolivar, I.; Karaplis, A.; Goltzman, D. Parathyroid Hormone-Related Peptide Interacts with Bone Morphogenetic Protein 2 to Increase Osteoblastogenesis and Decrease Adipogenesis in Pluripotent C3H10T½ Mesenchymal Cells. Endocrinology 2003, 144, 5511–5520.
  10. Zhang, X.; Cheng, Q.; Wang, Y.; Leung, P.S.; Mak, K.K. Hedgehog Signaling in Bone Regulates Whole-Body Energy Metabolism through a Bone–Adipose Endocrine Relay Mediated by PTHrP and Adiponectin. Cell Death Differ. 2017, 24, 225–237.
  11. Combs, T.P.; Berg, A.H.; Obici, S.; Scherer, P.E.; Rossetti, L. Endogenous Glucose Production Is Inhibited by the Adipose-Derived Protein Acrp30. J. Clin. Investig. 2001, 108, 1875–1881.
  12. Yamauchi, T.; Kamon, J.; Ito, Y.; Tsuchida, A.; Yokomizo, T.; Kita, S.; Sugiyama, T.; Miyagishi, M.; Hara, K.; Tsunoda, M.; et al. Cloning of Adiponectin Receptors That Mediate Antidiabetic Metabolic Effects. Nature 2003, 423, 762–769.
  13. Kir, S.; White, J.P.; Kleiner, S.; Kazak, L.; Cohen, P.; Baracos, V.E.; Spiegelman, B.M. Tumour-Derived PTH-Related Protein Triggers Adipose Tissue Browning and Cancer Cachexia. Nature 2014, 513, 100–104.
  14. De Jesus, L.A.; Carvalho, S.D.; Ribeiro, M.O.; Schneider, M.; Kim, S.-W.; Harney, J.W.; Larsen, P.R.; Bianco, A.C. The Type 2 Iodothyronine Deiodinase Is Essential for Adaptive Thermogenesis in Brown Adipose Tissue. J. Clin. Investig. 2001, 108, 1379–1385.
  15. Qin, B.; Qincao, L.; He, S.; Liao, Y.; Shi, J.; Xie, F.; Diao, N.; Bai, L. Parathyroid Hormone-Related Protein Prevents High-Fat-Diet-Induced Obesity, Hepatic Steatosis and Insulin Resistance in Mice. Endocr. J. 2022, 69, 55–65.
  16. Tezze, C.; Romanello, V.; Sandri, M. FGF21 as Modulator of Metabolism in Health and Disease. Front. Physiol. 2019, 10, 419.
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