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Its controversial pharmacology and often species-dependent regulation have impacted upon the potential translation of preclinical data involving GPR55.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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 specific for\n                      <jats:italic>GPR55<\/jats:italic>\n                      5\u2032-UTR, which allowed definition of the requirement of GPR55 Lys\n                      <jats:sup>80<\/jats:sup>\n                      for LPI-induced MAPK activation and receptor internalisation. In RAW264.7 macrophages, GPR55 pathways were investigated by\n                      <jats:italic>Gpr55<\/jats:italic>\n                      silencing using small-interfering RNAs, which demonstrated that LPI increased intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      levels and induced actin filopodium formation through GPR55 activation. Furthermore, the LPI\/GPR55 axis was shown to have an active role in osteoclastogenesis of precursor RAW264.7 cells induced by \u2018receptor-activator of nuclear factor kappa-\u03b2 ligand\u2019 (RANKL). Indeed, this differentiation into mature osteoclasts was associated with a 14-fold increase in\n                      <jats:italic>Gpr55<\/jats:italic>\n                      mRNA levels. Moreover, GPR55 silencing and antagonism impaired RANKL-induced transcription of the osteoclastogenesis markers: \u2018nuclear factor of activated T-cells, cytoplasmic 1\u2032, 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-specific peptide-P1 strongly inhibited osteoclast maturation of RAW264.7 macrophages, confirming its activity as a blocker of GPR55-mediated functions. Although osteoclast syncytium formation was not affected by pharmacological regulation of GPR55, osteoclast activity was dependent on GPR55 signalling, as shown with resorption assays on bone slices, where LPI stimulated and GPR55 antagonists inhibited bone erosion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12964-021-00727-w","type":"journal-article","created":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T04:03:33Z","timestamp":1619409813000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Peptide targeting of lysophosphatidylinositol-sensing GPR55 for osteoclastogenesis tuning"],"prefix":"10.1186","volume":"19","author":[{"given":"Maria Giovanna","family":"Mosca","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4524-6317","authenticated-orcid":false,"given":"Maria","family":"Mangini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefania","family":"Cioffi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pasquale","family":"Barba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6397-3016","authenticated-orcid":false,"given":"Stefania","family":"Mariggi\u00f2","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,4,26]]},"reference":[{"key":"727_CR1","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1038\/nrd.2017.178","volume":"16","author":"AS Hauser","year":"2017","unstructured":"Hauser AS, Attwood MM, Rask-Andersen M, Schioth HB, Gloriam DE. 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