The calcium‐sensing receptor and parathyroid hormone‐related protein are expressed in differentiated, favorable neuroblastic tumors

Abstract

Objective Lubricin, also referred to as superficial zone protein and PRG4, is a synovial glycoprotein that supplies a friction‐resistant, antiadhesive coating to the surfaces of articular cartilage, thereby protecting against arthritis‐associated tissue wear and degradation. This study was undertaken to generate and characterize a novel recombinant lubricin protein construct, LUB:1, and to evaluate its therapeutic efficacy following intraarticular delivery in a rat model of osteoarthritis (OA). Methods Binding and localization of LUB:1 to cartilage surfaces was assessed by immunohistochemistry. The cartilage‐lubricating properties of LUB:1 were determined using a custom friction testing apparatus. A cell‐binding assay was performed to quantify the ability of LUB:1 to prevent cell adhesion. Efficacy studies were conducted in a rat meniscal tear model of OA. One week after the surgical induction of OA, LUB:1 or phosphate buffered saline vehicle was administered by intraarticular injection for 4 weeks, with dosing intervals of either once per week or 3 times per week. OA pathology scores were determined by histologic analysis. Results LUB:1 was shown to bind effectively to cartilage surfaces, and facilitated both cartilage boundary lubrication and inhibition of synovial cell adhesion. Treatment of rat knee joints with LUB:1 resulted in significant disease‐modifying, chondroprotective effects during the progression of OA, by markedly reducing cartilage degeneration and structural damage. Conclusion Our findings demonstrate the potential use of recombinant lubricin molecules in novel biotherapeutic approaches to the treatment of OA and associated cartilage abnormalities.

Calcium-Sensing Receptor-Mediated Osteogenic and Early-Stage Neurogenic Differentiation in Umbilical Cord Matrix Mesenchymal Stem Cells from a Large Animal Model

“…Our observations of a synergic up-regulation of CaSR and the neurogenic biomarker Nestin mRNA levels, by both CaSR agonists (Ca 2+ and AMG641) and in both cell lines, even associated with non quantitatively relevant effects on Nissl bodies formation and beta III tubulin immunopositivity, support our hypothesis that CaSR is involved in early-stage neurogenic differentiation of UCM-MSCs, as reported in previous studies in other cell systems [72]. The stimulatory effects of the CaSR agonist observed in our study are also in line with those reported by Vizard et al, [45] who showed that activating CaSR in perinatal sympathetic neurons with the calcimimetic NPS R-467 enhances axonal and dendritic growth in culture and this effect is reversed by the selective CaSR antagonist NPS89636 and cannot be obtained in CaSR deficient mice.…”

Cinacalcet inhibits neuroblastoma tumor growth and upregulates cancer-testis antigens

“…This GPCR is also expressed in many organs not involved in calcium homeostasis and in some neoplasias in which it plays cell-type specific functions [13]. Our initial work showed that CaSR is expressed in benign, differentiated neuroblastic tumors and upregulated upon differentiation induction [14]. Next, we reported that the CaSR gene is silenced by genetic and epigenetic mechanisms in MYCN-amplified, unfavorable neuroblastomas [15].…”

“…Sections (4 μm) of formalin fixed, paraffinembedded tumors were stained with haematoxylin eosin (H&E), Masson's trichrome or processed for immunohistochemistry to analyze CaSR expression as described [14]. A similar protocol was carried out with antiGAGE7 (Life Technologies) and antihuman nuclei, clone 3E1.3 (MerckMillipore, Darmstadt, Germany).…”

“…Retrotranscription, PCR and qPCR were carried out as described [14,15]. Realtime PCR runs were performed in a 7500 SDS system using gene specific Assays on Demand and Taqman Universal PCR Master Mix, or specific primers (Supplementary Table S1) and SYBRGreen (Applied Biosystems, Forster City, CA).…”

Effects of parathyroid hormone-related protein and macrophage inflammatory protein-1α in Jurkat T-cells on tumor formationin vivoand expression of apoptosis regulatory genesin vitro

“…In fact, PTHrP has been shown to regulate cell growth, differentiation and survival [14]. Up-regulation of PTHrP in cancer cells has been demonstrated in breast, prostate and lung cancer, neuroblastic tumors, ATLL and other cancers [15]. PTHrP functions mainly by binding to its membrane receptor, PTH1R.…”