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Peptide Targeting of Lysophosphatidylinositol-Sensing GPR55 for Osteoclastogenesis Tuning

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Peptide Targeting of Lysophosphatidylinositol-Sensing GPR55 for Osteoclastogenesis Tuning Mosca et al. Cell Commun Signal (2021) 19:48 https://doi.org/10.1186/s12964-021-00727-w RESEARCH Open Access Peptide targeting of lysophosphatidylinositol-sensing GPR55 for osteoclastogenesis tuning Maria Giovanna Mosca1†, Maria Mangini1,3† , Stefania Ciof1,3, Pasquale Barba2 and Stefania Mariggiò1,3* Abstract Background: The G-protein-coupled receptor GPR55 has been implicated in multiple biological activities, which has fuelled interest in its functional targeting. Its controversial pharmacology and often species-dependent regulation have impacted upon the potential translation of preclinical data involving GPR55. Results: With the aim to identify novel GPR55 regulators, we have investigated lysophosphatidylinositol (LPI)- induced GPR55-mediated signal transduction. The expression system for wild-type and mutated GPR55 was HeLa cells silenced for their endogenous receptor by stable expression of a short-hairpin RNA specifc for GPR55 5′-UTR, which allowed defnition of the requirement of GPR55 Lys80 for LPI-induced MAPK activation and receptor internalisa- tion. In RAW264.7 macrophages, GPR55 pathways were investigated by Gpr55 silencing using small-interfering RNAs, 2 which demonstrated that LPI increased intracellular Ca + levels and induced actin flopodium formation through GPR55 activation. Furthermore, the LPI/GPR55 axis was shown to have an active role in osteoclastogenesis of precur- sor RAW264.7 cells induced by ‘receptor-activator of nuclear factor kappa-β ligand’ (RANKL). Indeed, this diferentiation into mature osteoclasts was associated with a 14-fold increase in Gpr55 mRNA levels. Moreover, GPR55 silencing and antagonism impaired RANKL-induced transcription of the osteoclastogenesis markers: ‘nuclear factor of activated T-cells, cytoplasmic 1′, matrix metalloproteinase-9, cathepsin-K, tartrate-resistant acid phosphatase, and the calcitonin receptor, as evaluated by real-time PCR. Phage display was previously used to identify peptides that bind to GPR55. Here, the GPR55-specifc peptide-P1 strongly inhibited osteoclast maturation of RAW264.7 macrophages, confrming its activity as a blocker of GPR55-mediated functions. Although osteoclast syncytium formation was not afected by pharmacological regulation of GPR55, osteoclast activity was dependent on GPR55 signalling, as shown with resorp- tion assays on bone slices, where LPI stimulated and GPR55 antagonists inhibited bone erosion. Conclusions: Our data indicate that GPR55 represents a target for development of novel therapeutic approaches for treatment of pathological conditions caused by osteoclast-exacerbated bone degradation, such as in osteoporosis or during establishment of bone metastases. Keywords: G-protein-coupled receptor (GPCR), GPR55, Lysophosphatidylinositol (LPI), Peptidic binder, Osteoclastogenesis Background G-protein-coupled receptors (GPCRs) are attractive *Correspondence: [email protected] targets for drug discovery as they regulate a vast array †Maria Giovanna Mosca and Maria Mangini contributed equally to this work of physiological processes and have accessible ‘drug- 1 Institute of Protein Biochemistry, National Research Council, Naples, Italy gable’ sites [1]. Furthermore, their pharmacological Full list of author information is available at the end of the article manipulation represents an already validated approach © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Mosca et al. Cell Commun Signal (2021) 19:48 Page 2 of 24 for treatment of numerous diseases. To date about 34% [33] and proliferation [34], neuropathic pain [35], bone of drugs on the market are directed towards GPCRs, remodelling [9] and cancer progression [36, 37]. and the targeting of these receptors was proposed to be Whyte and collaborators addressed the physiological promising also for cancer treatment [2]. An analysis of relevance of the LPI/GPR55 axis in bone metabolism [9]. all GPCR drugs in clinical trials highlighted the trends Indeed, a Gpr55-knockout mouse model showed a sig- across all molecule types, particularly in favour of bio- nifcant increase in volume and thickness of the trabecu- logics, allosteric modulators, and ligands with biased lar bone, and an excess of non-resorbed cartilage. Tey signalling [1]. demonstrated that this bone phenotype was consequent GPR55 belongs to the δ group of rhodopsin-like to increased numbers of morphologically inactive osteo- (Class A) GPCRs [3, 4], and the distribution of its clasts [9]. However, little is known about the mechanism mRNA expression has been detailed in diferent organ- of action of GPR55 in the osteoclastogenesis process. isms; however, information regarding the expression On the basis of the relevance of GPR55 in several bio- levels of the GPR55 protein is still lacking [5]. GPR55 logical functions, many eforts have been dedicated to its is widely expressed in several mammalian tissues, targeting. However, these have been challenged by the including breast, adipose tissue, testes and spleen [6], difculties arisen from GPR55 complicated pharmacol- and several regions of the brain [7]. GPR55 has been ogy and its often species-dependent regulation. Tis has implicated in diferent pathophysiological conditions, made difcult to understand the potential for its transla- such as vascular functions [8], bone turnover [9, 10], tion to the clinic [5]. neuropathic/infammatory pain [11, 12], motor coordi- Here we have dissected out LPI-activated GPR55 sig- nation [13], central nervous system disorders [14, 15], nalling, which highlights the requirement of GPR55 Lys80 metabolic dysfunction [5, 16], immune dysregulation for LPI recognition, and the relevance of the LPI/GPR55 [17] and alterations that drive malignant cell growth axis in the osteoclastogenesis process and in osteoclast [18, 19]. bone resorption. Furthermore, we have characterised a For a long time, GPR55 was classifed as a cannabinoid peptide that specifcally recognises and binds to GPR55, receptor [20], as after its discovery and cloning [21], dif- as both the human and murine receptor. Tis provides an ferent studies demonstrated that endogenous, plant and example of a valuable tool with potential application to synthetic cannabinoids can bind to and activate GPR55 targeted and combination therapies in bone pathologies [22]. However, GPR55 is phylogenetically distinct from with exacerbated osteoclast activity. the traditional cannabinoid receptors, and human GPR55 Materials and methods shows only 13.5% and 14.4% homology with human CB 1 Materials and CB2, respectively [20]. Subsequent in-vitro screening led to identifcation of new GPR55 ligands that are unre- Dulbecco’s modifed Eagle’s medium (DMEM), mini- lated to the cannabinoid system [23–28]. Furthermore, mum essential medium (MEM), foetal bovine serum the International Union of Basic and Clinical Pharmacol- (FBS), non-essential amino acids, Hanks balanced ogy (IUPHAR) still classifes GPR55 as an orphan recep- salt solution with calcium and magnesium (HBSS ++), tor, with lysophosphatidylinositol (LPI), and in particular and phosphate-bufered saline (PBS) were from Gibco 2-arachidonoylglycerolphosphoinositol [29], proposed (Life Technologies Italia, Italy). Penicillin–streptomy- as the natural/endogenous ligand [30]. Indeed, LPI has cin, L-glutamine, non-fat milk, bovine serum albumin been shown to bind to and activate GPR55 in vitro [20, (BSA), fatty-acid-free (faf)-BSA, Tween-20, MEM Eagle 31], although whether this activation occurs in vivo is still alpha-modifed (α-MEM), Hoechst, CID16020046, under investigation [30]. and L-α-lysophosphatidylinositol sodium salt from Te LPIs are a group of lysolipids that are characterised soybean were from Sigma-Aldrich (St. Louis, MO, by a glycerol backbone with a single fatty acid substitu- USA). Purifed synthetic 1-palmitoyl-2-hydroxy-sn- tion, which is linked to the myo-inositol molecule by a glycero-3-phosphoinositol (16:0 LPI), 1-stearoyl- phosphodiester bond [32]. Te acyl chain can be diferent 2-hydroxy-sn-glycero-3-phosphoinositol (18:0 LPI), depending on its position on the glycerol backbone, its 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-(1′-myo- length, and the number of its unsaturated bonds. LPI can inositol) (18:1 LPI), 1-arachidonoyl-2-hydroxy-sn-glyc- be produced from the membrane component phosphati- ero-3-phosphoinositol (20:4 LPI) were from Avanti Polar dylinositol by the catalytic activity of phospholipases A1 Lipids, Inc. (Alabaster, AL, USA). ML-191, ML-184, or A2, which catalyse the hydrolysis of the
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