title: Proline/arginine-rich end leucine-rich repeat protein N-terminus is a novel osteoclast antagonist that counteracts bone loss.
abstract: (hbd) PRELP is a peptide corresponding to the N-terminal heparin binding domain of the matrix protein proline/arginine-rich end leucine-rich repeat protein (PRELP). (hbd) PRELP inhibits osteoclastogenesis entering pre-fusion osteoclasts through a chondroitin sulfate- and annexin 2-dependent mechanism and reducing the nuclear factor-κB transcription factor activity. In this work, we hypothesized that (hbd) PRELP could have a pharmacological relevance, counteracting bone loss in a variety of in vivo models of bone diseases induced by exacerbated osteoclast activity. In healthy mice, we demonstrated that the peptide targeted the bone and increased trabecular bone mass over basal level. In mice treated with retinoic acid to induce an acute increase of osteoclast formation, the peptide consistently antagonized osteoclastogenesis and prevented the increase of the serum levels of the osteoclast-specific marker tartrate-resistant acid phosphatase. In ovariectomized mice, in which osteoclast activity was chronically enhanced by estrogen deficiency, (hbd) PRELP counteracted exacerbated osteoclast activity and bone loss. In mice carrying osteolytic bone metastases, in which osteoclastogenesis and bone resorption were enhanced by tumor cell-derived factors, (hbd) PRELP reduced the incidence of osteolytic lesions, both preventively and curatively, with mechanisms involving impaired tumor cell homing to bone and tumor growth in the bone microenvironment. Interestingly, in tumor-bearing mice, (hbd) PRELP also inhibited breast tumor growth in orthotopic sites and development of metastatic disease in visceral organs, reducing cachexia and improving survival especially when administered preventively. (hbd) PRELP was retained in the tumor tissue and appeared to affect tumor growth by interacting with the microenvironment rather than by directly affecting the tumor cells. Because safety studies and high-dose treatments revealed no adverse effects, (hbd) PRELP could be employed as a novel biological agent to combat experimentally induced bone loss and breast cancer metastases, with a potential translational impact.
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Rucci
authors.forename: Mattia
authors.initials: M
authors.lastname: Capulli
authors.forename: Luca
authors.initials: L
authors.lastname: Ventura
authors.forename: Adriano
authors.initials: A
authors.lastname: Angelucci
authors.forename: Barbara
authors.initials: B
authors.lastname: Peruzzi
authors.forename: Viveka
authors.initials: V
authors.lastname: Tillgren
authors.forename: Maurizio
authors.initials: M
authors.lastname: Muraca
authors.forename: Dick
authors.initials: D
authors.lastname: Heinegård
authors.forename: Anna
authors.initials: A
authors.lastname: Teti
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D001862:Bone Resorption / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D006023:Glycoproteins / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000150:complications / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010024:Osteoporosis / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C096382:PRELP protein, human
keywords: BONE LOSS; BREAST CANCER METASTASIS; OSTEOPOROSIS; hbdPRELP