Role Of Parathyroid Hormone-related Protein Research Articles

PTHrP participates in the bone destruction of middle ear cholesteatoma via promoting macrophage differentiation into osteoclasts induced by RANKL.

Progressive bone resorption and destruction is one of the most critical clinical features of middle ear cholesteatoma, potentially leading to various intracranial and extracranial complications. However, the mechanisms underlying bone destruction in middle ear cholesteatoma remain unclear. This study aims to explore the role of parathyroid hormone-related protein (PTHrP) in bone destruction associated with middle ear cholesteatoma. A total of 25 cholesteatoma specimens and 13 normal external auditory canal skin specimens were collected from patients with acquired middle ear cholesteatoma. Immunohistochemical staining was used to detect the expressions of PTHrP, receptor activator for nuclear factor-kappa B ligand (RANKL), and osteoprotegerin (OPG) in cholesteatoma and normal tissues. Tartrate-resistant acid phosphatase (TRAP) staining was used to detect the presence of TRAP positive multi-nucleated macrophages in cholesteatoma and normal tissues. Mono-nuclear macrophage RAW264.7 cells were subjected to interventions, divided into a RANKL intervention group and a PTHrP+ RANKL co-intervention group. TRAP staining was used to detect osteoclast formation in the 2 groups. The mRNA expression levels of osteoclast-related genes, including TRAP, cathepsin K (CTSK), and nuclear factor of activated T cell cytoplasmic 1 (NFATc1), were measured using real-time polymerase chain reaction (real-time PCR) after the interventions. Bone resorption function of osteoclasts was assessed using a bone resorption pit analysis. Immunohistochemical staining showed significantly increased expression of PTHrP and RANKL and decreased expression of OPG in cholesteatoma tissues (all P<0.05). PTHrP expression was significantly positively correlated with RANKL, the RANKL/OPG ratio, and negatively correlated with OPG expression (r=0.385, r=0.417, r=-0.316, all P<0.05). Additionally, the expression levels of PTHrP and RANKL were significantly positively correlated with the degree of bone destruction in cholesteatoma (r=0.413, r=0.505, both P<0.05). TRAP staining revealed a large number of TRAP-positive cells, including multi-nucleated osteoclasts with three or more nuclei, in the stroma surrounding the cholesteatoma epithelium. After 5 days of RANKL or PTHrP+RANKL co-intervention, the number of osteoclasts was significantly greater in the PTHrP+RANKL co-intervention group than that in the RANKL group (P<0.05), with increased mRNA expression levels of TRAP, CTSK, and NFATc1 (all P<0.05). Scanning electron microscopy of bone resorption pits showed that the number (P<0.05) and size of bone resorption pits on bone slices were significantly greater in the PTHrP+RANKL co-intervention group compared with the RANKL group. PTHrP may promote the differentiation of macrophages in the surrounding stroma of cholesteatoma into osteoclasts through RANKL induction, contributing to bone destruction in middle ear cholesteatoma.

Role of parathyroid hormone-related protein in breast cancer detection and prognosis

Currently, there are limited data supporting the use of parathyroid hormone-related protein for the purposes of breast cancer detection and disease prognosis. This literature review covers research results on diagnostic potential of parathyroid hormone-related protein as a biomarker for breast cancer, as well as the information available in the scientific literature, reflecting obvious contradictions regarding clinical and prognostic importance of this protein in the primary breast cancer, correlation of its expression with the risk of bone metastasis and survival of patients. Results of preclinical and clinical research show, that parathyroid hormone-related protein inhibits tumor progression and decreases its metastasis at early stages of the disease, which improves the survival rate, but it has an opposite effect at the advanced stages of cancer, as it increases tumor development and metastasis, and reduces survival rates. Altogether, these studies prove an idea that parathyroid hormone-related protein plays a double role in breast cancer. Use of parathyroid hormone-related protein for breast cancer early detection and disease prognosis is currently becoming a subject of detailed scientific research studies, which is confirmed by the facts presented in this literature review.

Role of PTHrP in attenuating transient pressure rises and associated afferent nerve activity of the rat bladder.

Parathyroid hormone-related protein (PTHrP) released from detrusor smooth muscle (DSM) as the bladder fills acts as an endogenous DSM relaxant to facilitate bladder storage function. Here, the effects of exogenous PTHrP on transient pressure rises (TPRs) in the bladder and associated afferent nerve activity during bladder filling were investigated. In anaesthetized rats, changes in the intravesical pressure were measured while the bladder was gradually filled with saline. Afferent nerve activity was simultaneously recorded from their centrally disconnected left pelvic nerves. In DSM strips, spontaneous and nerve-evoked contractions were isometrically recorded. The distribution of PTHrP receptors (PTHrPRs) in the bladder wall was also examined by fluorescence immunostaining. The bladders in which the contralateral pelvic nerve was also centrally disconnected developed nifedipine, an L-type voltage-dependent Ca2+ channel blocker-sensitive TPRs (< 3mmHg). Intravenous administration of PTHrP suppressed these TPRs and associated bursts of afferent nerve activity. In the bladders with centrally connected contralateral pelvic nerves, atropine, a muscarinic receptor antagonist-sensitive large TPRs (> 3mmHg) developed in the late filling phase. PTHrP diminished the large TPRs and corresponding surges of afferent nerve activity. In DSM strips, bath-applied PTHrP (10nM) suppressed spontaneous phasic contractions, while less affecting nerve-evoked contractions. PTHrPRs were expressed in DSM cells but not in intramural nerve fibers. Thus, PTHrP appears to suppress bladder TPRs and associated afferent nerve activity even under the influence of low degree of parasympathetic neural input during storage phases. Endogenous PTHrP may indirectly attenuate afferent nerve activity by suppressing TPRs to facilitate urinary accommodation.

Roles of Parathyroid Hormone-Related Protein (PTHrP) and Its Receptor (PTHR1) in Normal and Tumor Tissues: Focus on Their Roles in Osteosarcoma.

Osteosarcoma (OS) is the most common primary bone tumor and originates from bone forming mesenchymal cells and primarily affects children and adolescents. The 5-year survival rate for OS is 60 to 65%, with little improvement in prognosis during the last four decades. Studies have demonstrated the evolving roles of parathyroid hormone-related protein (PTHrP) and its receptor (PTHR1) in bone formation, bone remodeling, regulation of calcium transport from blood to milk, regulation of maternal calcium transport to the fetus and reabsorption of calcium in kidneys. These two molecules also play critical roles in the development, progression and metastasis of several tumors such as breast cancer, lung carcinoma, chondrosarcoma, squamous cell carcinoma, melanoma and OS. The protein expression of both PTHrP and PTHR1 have been demonstrated in OS, and their functions and proposed signaling pathways have been investigated yet their roles in OS have not been fully elucidated. This review aims to discuss the latest research with PTHrP and PTHR1 in OS tumorigenesis and possible mechanistic pathways.This review is dedicated to Professor Michael Day who died in May 2020 and was a very generous collaborator.

Parathyroid hormone-related protein as predictor of urolithiasis disease development

Background. The present article studies a possible role of parathyroid hormone-related protein (PTHrP) in urolithiasis pathogenesis.Aim. To consider PTHrP level as a predictor of the urolithiasis development.Material and methods. We presented an analysis of treatment in 79 patients with primary and recurrent nephrolithiasis that had underwent surgical treatment in the Uronephrological Center of Scientific Research Institute – Ochapovsky Regional Clinical Hospital #1, Krasnodar from 2017 to 2019. All observed patients were divided in two groups: patients with primary and recurrent nephrolithiasis. A group of 10 relatively healthy people was included in the study as well. All patients and conditionally healthy people had a test for blood parameters; in particular, the level of parathyroid hormone-related protein was assessed in order to compare the indicators in all three groups.Conclusions. The PTHrP level was showed to be statistically significantly different in patients with urolithiasis from the group with relatively healthy people. Groups with primary and recurrent nephrolithiasis show not difference in the level of PTHrP. Further studies are necessary to consider this protein as one of the predictors of urolithiasis and study its role in the pathogenesis of nephrolithiasis.

Parathyroid hormone receptor 1 (PTHR1) is a prognostic indicator in canine osteosarcoma

Osteosarcoma (OS) is the most common malignant primary bone tumour in humans and dogs. Several studies have established the vital role of parathyroid hormone-related protein (PTHrP) and its receptor (PTHR1) in bone formation and remodeling. In addition, these molecules play a role in the progression and metastasis of many human tumour types. This study investigated the expression of PTHR1 and PTHrP in canine OS tissues and assessed their prognostic value. Formalin-fixed, paraffin-embedded tissue samples from 50 dogs diagnosed with primary OS were immunolabeled with antibodies specific for PTHR1 and PTHrP. The immunostaining intensity of tumours from patients with OS was correlated with survival time. Both PTHR1 and PTHrP were detected in all OS samples (n = 50). Dogs with OS tumours showing high immunostaining intensity for PTHR1 (n = 36) had significantly shorter survival times (p = 0.028, Log Rank; p = 0.04, Cox regression) when compared with OS that had low immunostaining intensity for PTHR1 (n = 14).PTHrP immunostaining intensity did not correlate with survival time (p > 0.05). The results of this study indicate that increased expression of PTHR1 antigen in canine OS is associated with poor prognosis. This suggests that PTHR1 may be useful as a prognostic indicator in canine OS.

Parathyroid Hormone-Related Protein (PTHrP) Accelerates Soluble RANKL Signals for Downregulation of Osteogenesis of Bone Mesenchymal Stem Cells.

A recent study reported the expression of receptor activator of nuclear factor-κB (RANK) in mesenchymal stem cells (MSCs) surface that negatively regulates osteogenesis of MSCs. Empirical evidence from the previous study confirmed the role of parathyroid hormone-related protein (PTHrP) in osteoblastogenesis. However, it is necessary to understand the paracrine role of PTHrP and RANKL for osteogenesis in order to explore the hidden secrets in bone biology. Considering the above concept, paracrine cues of soluble-receptor activator of nuclear factor-κB ligand (sRANKL) and PTHrP in osteogenic differentiation of MSCs were investigated. Our results confirmed that sRANKL increased the expression of surface-RANK in MSCs at the earlier stage of osteogenesis, which was downregulated later in differentiated MSCs. In contrast, RANKL expression was low at the earlier stage of MSCs proliferation and high at the differentiation stage of MSCs, which may play a fundamental role in osteoclast formation. sRANKL downregulated osteogenesis of MSCs by decreasing progressive ankylosis (ANK) protein expression while PTHrP upregulated the osteogenic exploitive effect of sRANKL. Interestingly, when they were co-cultured with MSCs, T-lymphocytes expressed high membrane-RANKL levels that contribute to osteogenesis inhibition during MSC differentiation. Thus, our results disclose that sRANKL treatment downregulates osteogenesis of MSCs by increasing RANK expression at the earlier stage of differentiation and by inhibiting ANK. Further, we demonstrated that PTHrP accelerated the downregulating osteogenic effect of sRANKL.

Physiological roles of parathyroid hormone-related protein.

Background: Parathyroid hormone related peptide (PTHrP) is widely expressed in a variety of normal fetal and adult tissues. Aim of work: Review of these normal physiologic functions of PTHrP in each of these tissues. Method: Performed literature search on pubmed on articles related to PTHrP and physiologic roles. Results: PTHrP is expressed in wide range of sites in the body with roles including relaxation of vessels and smooth muscle cells, and regulation of development. PTHrP also mediates humoral hypercalcemia of malignancy. PTHrP can be falsely elevated in benign conditions. Lastly, PTHrP has a pharmacological role in osteoporosis treatment. Conclusions: PTHrP has many various physiological roles besides mediating humoral hypercalcemia of malignancy. (www.actabiomedica.it)

Abstract 2632: Identification of PTHrP as a biomarker of short survival &amp; brain metastasis in a tissue microarray retrospective analysis of triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) represents 10-20% of all BC cases, and is characterized by aggressive clinical course, frequent relapse, poor patient outcome, and lack of targeted therapy due to the lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2). Identifying TNBC molecular drivers and biomarkers would thus be highly beneficial to develop efficient targeted therapies. The parathyroid hormone-related protein (PTHrP) is known for its role in mammary gland and bone development, in addition to breast cancer progression. The aim of this study is to investigate the role of PTHrP as a potential prognostic biomarker in human TNBC. We assessed PTHrP expression using immunohistochemical analysis of a tissue microarray (TMA) constructed for 523 patients newly diagnosed with TNBC between January 1998 and December 2008 in a single-center series with centralized ER, PR and HER-2 testing and standardized treatment and follow-up. We evaluated the correlation between PTHrP expression and TNBC patients' clinico-pathological features as well as progression and survival outcomes for a subset of 314 patients with available clinical data. We show that PTHrP is overexpressed in 55.2% of TNBC tumors and high PTHrP expression is significantly associated with higher propensity for brain progression compared to other sites of distal progression (p=0.0458). Univariate analysis revealed that high PTHrP expression is significantly associated with decreased overall survival (OS) (p=0.0055), but not with progression-free survival (PFS) (p=0.1270). To further investigate the prognostic value of PTHrP with respect to different TNBC molecular subtypes, we analysed expression of markers known to stratify different TNBC subtypes. Multivariate analysis of PTHrP as an independent prognostic factor of survival with respect to different TNBC molecular subtypes is currently underway. In conclusion, we provide for the first time evidence that increased PTHrP expression is significantly associated with shorter OS and higher propensity of brain progression in patients diagnosed with TNBC. Consequently, stratification of this disease based on PTHrP expression might identify patients with relatively higher risk of aggressive disease with brain progression. Additional studies investigating the role of PTHrP in organ-specific metastasis and using PTHrP-targeting strategies are warranted to improve the therapeutic outcome for patients diagnosed with TNBC. Funding: Alberta Cancer Research Institute (ACRI) grant and Department of Defense (DoD, USA) Award No. W81XWH-15-1-0723 Citation Format: Gloria Assaker, Anne Camirand, Bassam Abdulkarim, Atilla Omeroglu, Jean Deschenes, Leon Van Kempen, Richard Kremer, Siham Sabri. Identification of PTHrP as a biomarker of short survival &amp; brain metastasis in a tissue microarray retrospective analysis of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2632.

THE ROLE OF PARATHYROID HORMONE-RELATED PROTEIN IN PATHOGENESIS OF DISORDERS OF BLADDER CONTRACTILE FUNCTION

Aim. Based on the analysis of the scientific literature sources, the authors aimed to summarize and present the existing information about the role of parathyroid hormone-related protein (PTHrP) in pathogenesis of disorders of bladder contractile function. Materials and methods . Analysis of literature in databases Google Scholar, Scopus, Web of Scence, PabMed for the whole time period of studying the stated problem. Results . In the recent years, one can observe a growing interest to dysfunction of bladder with insuffi contractile activity of detrusor. The low level activity of bladder can be often observed, while its diagnostics and treatment remain problematic. The existing ideas about the role of parathyroid hormone-related protein (PTHrP) in regulation of bladder’s functional condition are based on the results of few and mostly experimental research studies. It is proved that PTHrP secretion is induced in bladder as a result of bladder stretching, and prevents spontaneous contraction of detrusor’s smooth muscles, which has PTH/PTHrPreceptors, and also reduces contraction amplitude of bladder. It was stated that increased PTHrP secretion in response to the stretching smooth muscles is a part of autocrine effect, relaxing the bladder during its fi The existing scientifi data show that PTHrP is a unique endogenous detrusor relaxant, which functions by means of PTH/PTHrP-receptors located in bladder. It is assumed that PTHrP can also have a paracrine effect on vessels that regulate the blood fl bladder fi or can change neural activity. Thus, PTHrP is a powerful endogenous relaxant of bladder contraction, while autocrine or paracrine mechanisms of this effect are physiologically relevant processes happening in bladder. It is assumed that disturbed binding PTHrP with its receptor can be part ofpathogenesis of bladder disorders. In our opinion, the infl of chronic high PTHrP level in blood fl on the detrusor muscle structures can be also considered as one of the reasons that cause functional insuffi of bladder. This assumption is based on comparison of the PTHrP-effects on the bladder functional condition, presented in the experiment, as well as in the few clinical studies. Direct infl targeting the interaction of PTHrP with its specifi PTH/PTHrP-receptor is considered as a potential therapeutic approach to treat pathological conditions related to disorder of bladder contractile function. Conclusion . The literature survey covers general ideas about functional insufficiency of bladder, as well as information about the role of PTHrP in its development. The studied problem is rather relevant and frequent in the population, and besides being seen as a urological pathology, it is associated with a considerable reduction of the quality of life for patients. More detailed clinical studies will let us specify the diagnostics criteria of this syndrome and develop the schemes for pathogenetic therapy .

Dual roles of parathyroid hormone related protein in TGF-β1 signaling and fibronectin up-regulation in mesangial cells.

Little is known about the cross-talk between parathyroid hormone (PTH) related protein (PTHrP) and TGF-β1 in mesangial cells (MCs). Our results showed that PTHrP treatment (≤3 h) induced internalization of PTH1R (PTH/PTHrP receptor)–TβRII (TGF-β type 2 receptor) complex and suppressed TGF-β1-mediated Smad2/3 activation and fibronectin (FN) up-regulation. However, prolonged PTHrP treatment (12–48 h) failed to induce PTH1R–TβRII association and internalization. Total protein levels of PTH1R and TβRII were unaffected by PTHrP treatment. These results suggest that internalization of PTH1R and TβRII after short PTHrP treatment might not lead to their proteolytic destruction, allowing the receptors to be recycled back to the plasma membrane during prolonged PTHrP exposure. Receptor re-expression at the cell surface allows PTHrP to switch from its initial inhibitory effect to promote induction of FN. Our study thus demonstrates the dual roles of PTHrP on TGF-β1 signaling and FN up-regulation for the first time in glomerular MCs. These data also provided new insights to guide development of therapy for diabetic kidney disease (DKD).

The Role of Parathyroid Hormone-Related Protein (PTHrP) in Osteoblast Response to Microgravity: Mechanistic Implications for Osteoporosis Development.

Prolonged skeletal unloading through bedrest results in bone loss similar to that observed in elderly osteoporotic patients, but with an accelerated timeframe. This rapid effect on weight-bearing bones is also observed in astronauts who can lose up to 2% of their bone mass per month spent in Space. Despite the important implications for Spaceflight travelers and bedridden patients, the exact mechanisms involved in disuse osteoporosis have not been elucidated. Parathyroid hormone-related protein (PTHrP) regulates many physiological processes including skeletal development, and has been proposed as a mechanosensor. To investigate the role of PTHrP in microgravity-induced bone loss, trabecular and calvarial osteoblasts (TOs and COs) from Pthrp +/+ and -/- mice were subjected to actual Spaceflight for 6 days (Foton M3 satellite). Pthrp +/+, +/- and -/- osteoblasts were also exposed to simulated microgravity for periods varying from 6 days to 6 weeks. While COs displayed little change in viability in 0g, viability of all TOs rapidly decreased in inverse proportion to PTHrP expression levels. Furthermore, Pthrp+/+ TOs displayed a sharp viability decline after 2 weeks at 0g. Microarray analysis of Pthrp+/+ TOs after 6 days in simulated 0g revealed expression changes in genes encoding prolactins, apoptosis/survival molecules, bone metabolism and extra-cellular matrix composition proteins, chemokines, insulin-like growth factor family members and Wnt-related signalling molecules. 88% of 0g-induced expression changes in Pthrp+/+ cells overlapped those caused by Pthrp ablation in normal gravity, and pulsatile treatment with PTHrP1-36 not only reversed a large proportion of 0g-induced effects in Pthrp+/+ TOs but maintained viability over 6-week exposure to microgravity. Our results confirm PTHrP efficacy as an anabolic agent to prevent microgravity-induced cell death in TOs.

The parathyroid hormone-related protein is secreted during the osteogenic differentiation of human dental follicle cells and inhibits the alkaline phosphatase activity and the expression of DLX3.

The dental follicle is involved in tooth eruption and it expresses a great amount of the parathyroid hormone-related protein (PTHrP). PTHrP as an extracellular protein is required for a multitude of different regulations of enchondral bone development and differentiation of bone precursor cells and of the development of craniofacial tissues. The dental follicle contains also precursor cells (DFCs) of the periodontium. Isolated DFCs differentiate into periodontal ligament cells, alveolar osteoblast and cementoblasts. However, the role of PTHrP during the human periodontal development remains elusive. Our study evaluated the influence of PTHrP on the osteogenic differentiation of DFCs under in vitro conditions for the first time. The PTHrP protein was highly secreted after 4days of the induction of the osteogenic differentiation of DFCs with dexamethasone (2160.5pg/ml±345.7SD. in osteogenic differentiation medium vs. 315.7pg/ml±156.2SD. in standard cell culture medium; Student's t Test: p<0.05 (n=3)). We showed that the supplementation of the osteogenic differentiation medium with PTHrP inhibited the alkaline phosphatase activity and the expression of the transcription factor DLX3, but the depletion of PTHrP did not support the differentiation of DFCs. Previous studies have shown that Indian Hedgehog (IHH) induces PTHrP and that PTHrP, in turn, inhibits IHH via a negative feedback loop. We showed that SUFU (Suppressor Of Fused Homolog) was not regulated during the osteogenic differentiation in DFCs. So, neither the hedgehog signaling pathway induced PTHrP nor PTHrP suppressed the hedgehog signaling pathway during the osteogenic differentiation in DFCs. In conclusion, our results suggest that PTHrP regulates independently of the hedgehog signaling pathway the osteogenic differentiated in DFCs.

Periosteal PTHrP Regulates Cortical Bone Remodeling During Fracture Healing

Parathyroid hormone-related protein (PTHrP) is widely expressed in the fibrous outer layer of the periosteum (PO), and the PTH/PTHrP type I receptor (PTHR1) is expressed in the inner PO cambial layer. The cambial layer gives rise to the PO osteoblasts (OBs) and osteoclasts (OCs) that model/remodel the cortical bone surface during development as well as during fracture healing. PTHrP has been implicated in the regulation of PO modeling during development, but nothing is known as regards a role of PTHrP in this location during fracture healing.We propose that PTHrP in the fibrous layer of the PO may be a key regulatory factor in remodeling bone formation during fracture repair. We first assessed whether PTHrP expression in the fibrous PO is associated with PO osteoblast induction in the subjacent cambial PO using a tibial fracture model in PTHrP-lacZ mice. Our results revealed that both PTHrP expression and osteoblast induction in PO were induced 3days post-fracture. We then investigated a potential functional role of PO PTHrP during fracture repair by performing tibial fracture surgery in 10-week-old CD1 control and PTHrP conditional knockout (PTHrP cKO) mice that lack PO PTHrP. We found that callus size and formation as well as woven bone mineralization in PTHrP cKO mice were impaired compared to that in CD1 mice. Concordant with these findings, functional enzyme staining revealed impaired OB formation and OC activity in the cKO mice.We conclude that deleting PO PTHrP impairs cartilaginous callus formation, maturation and ossification as well as remodeling during fracture healing. These data are the initial genetic evidence suggesting that PO PTHrP may induce osteoblastic activity and regulate fracture healing on the cortical bone surface.

Parathyroid Hormone-Related Protein: Not Just a Parathyrin Mimic but a Key Regulator of Diverse Tissues and Physiological Systems

Prior to the cloning of parathyroid hormone-related protein (PTHrP), three clinical scenarios predicted its existence. First was humoral hypercalcemia of malignancy (HHM), in which the skeleton is resorbed by a circulating factor whose tissue source may not be within bone. Although HHM resembles many aspects of primary hyperparathyroidism, parathyroid hormone (PTH) is undetectable. Second was a consistent discrepancy in newborn cord blood: low to undetectable immunoreactive levels of PTH, but high levels of PTH-like bioactivity in cytochemical assays. Third was that hypoparathyroid and aparathyroid women normalize mineral homeostasis during lactation and become hypercalcemic unless their supplemental calcium and calcitriol are discontinued. All three scenarios display biochemical results that are consistent with a circulating PTH-like hormone that binds to the PTH receptor and mimics the actions of PTH. Investigators focused on the cancer angle, and in 1987, three groups independently announced that they had cloned PTHrP from the picomolar or lesser amounts secreted from precious fragments of HHM-causative tumors. Soon enough, it became clear that increased circulating levels of PTHrP explained all three clinical scenarios. And to the chagrin of those researchers, they later learned that 1,000–10,000 times the amount of the elusive PTHrP had been more readily and cheaply recoverable from milk—whether in the local corner store, or produced by breastfeeding women! In the elapsed decades, it has become clear that PTHrP is also expressed in many tissues, wherein it has key paracrine and autocrine roles to regulate diverse tissues and cells. We have surveyed a select number of those roles in the following articles: Danks, Freeman and Martin provide an overview on the evolutionary origins and roles of PTHrP, PTH, and related gene products. Wright and Guise explain how PTHrP is both a locally secreted factor that enables tumors to carve out a niche for themselves within the skeleton and a systemically secreted factor that can lead to its classic presentation in HHM. Ohba and Chung detail the role that PTHrP plays in regulating the development of the endochondral skeleton. Kovacs describes the adaptive roles that PTHrP has to regulate mineral homeostasis in the mother during pregnancy and lactation and in the offspring during fetal and early neonatal development. Vasavada’s colleagues explain how PTHrP is expressed within pancreatic beta cells and contributes to the regulation of insulin and glucose homeostasis. Hiremath and Wysolmerski point out how PTHrP plays critical roles at all stages of breast development and physiology: from nipple bud to lactating breast and from normal to cancerous tissue. Finally, Towler provides an overview of our understanding of PTHrP’s role in regulating vascular smooth muscle and, thereby, blood pressure and vascular calcifications. Through these articles, it should become clear that PTHrP is not simply a parathyrin mimic. Nor is it a jack-ofall-trades. Instead, it is a key regulator of diverse tissues and physiological systems. In each system, PTHrP may become a treatment target, whether it is to boost, reduce, or block PTHrP signaling as needed to address the underlying clinical disorder. C. S. Kovacs (&) Faculty of Medicine—Endocrinology, Health Sciences Centre, Memorial University of Newfoundland, 300 Prince Philip Drive, St. John’s, NL A1B 3V6, Canada e-mail: ckovacs@mun.ca

Role of PTHrP in Mammary Gland Development and Breast Cancer

Parathyroid hormone-related protein (PTHrP) signaling has been shown to affect the development of many tissues including bone, cartilage, and mammary gland. In this review, we focus on the role of PTHrP in the normal mammary gland and its contributions to breast pathogenesis. During embryonic mammary development, PTHrP drives mammary mesenchyme specification, which is responsible for maintaining mammary cell fate, promoting the outgrowth of ducts, and directing the formation of the nipple. During lactation, PTHrP mobilizes maternal calcium to ensure a supply of calcium into milk and may play a role in regulating neonatal bone and mineral metabolism. PTHrP is expressed in primary breast cancer and breast cancer metastases, and contributes to the formation of osteolytic bone lesions as well as the growth and progression of primary tumors.

The Role of PTHrP in Pancreatic Beta-Cells and Implications for Diabetes Pathophysiology and Treatment

Diabetes is one of the fastest growing diseases worldwide, with an immense economic and health burden attached. It is now well accepted that a deficiency of functional insulin-producing pancreatic beta-cells is the main cause for all forms of diabetes. Several approaches are being taken to increase functional beta-cell mass. These include differentiation of new beta-cells from stem cells or progenitor cells, transdifferentiation of beta-cells from other mature cell types, as well as finding ways to enhance the function, proliferation, survival, and regeneration of preexisting beta-cells. This article enumerates on the role of parathyroid hormone-related protein (PTHrP) and its mode of action on pancreatic beta-cell function, proliferation, and survival in rodents as well as in human beta-cells. A further understanding of the mechanism of action of PTHrP and its role in the normal physiology and pathophysiology of the beta-cell will be important for its potential use in future as a therapeutic treatment for diabetes.

The Role of PTHrP in Skeletal Metastases and Hypercalcemia of Malignancy

Since its discovery as the principal mediator of humoral hypercalcemia of malignancy, parathyroid hormone-related protein (PTHrP) has emerged as a key player in skeletal complications associated with solid tumor metastasis to bone. In addition to functioning as an endocrine factor, this pleiotropic peptide mediates its actions locally on tumor and stromal cells in paracrine, autocrine, and intracrine fashion when cancer metastasizes to the bone compartment. Multiple splice variants and newly described PTHrP fragments confer diverse functions to PTHrP that extend beyond binding to its common receptor with parathyroid hormone. Here, we summarize the causal role of PTHrP in humoral hypercalcemia of malignancy and its local involvement in the progression of osteolytic and osteoblastic cancer bone metastases. Clinical and preclinical findings describing how PTHrP regulates tumor and stromal cell interactions are summarized, with emphasis on emerging evidence of PTHrP’s role in tumorigenesis and cancer cell proliferation. Finally, we examine therapeutic opportunities and limitations to targeting PTHrP directly and indirectly in cancer patients.

The Role of PTHrP in Regulating Mineral Metabolism During Pregnancy, Lactation, and Fetal/Neonatal Development

Parathyroid hormone-related protein (PTHrP) was originally identified as the cause of humoral hypercalcemia of malignancy (HHM), a condition that resembles primary hyperparathyroidism and the effects of excess parathyroid hormone (PTH). But HHM is an unusual situation because PTHrP is normally undetectable in the circulation of the child or adult. Instead, most of PTHrP’s actions are now understood to be paracrine or autocrine, and not humoral. However, PTHrP is present in the circulation at measurable levels during fetal development, pregnancy, and lactation. During these time periods, PTHrP has humoral actions that regulate mineral and bone homeostasis independently of PTH. In fact, the existence of PTHrP was also predicted by the characteristic pattern of serum chemistries and PTH in cord blood of normal newborns, and by the normalization of calcium metabolism that temporarily occurs in hypoparathyroid women who breast-feed. This article reviews our present understanding about PTHrP’s role to control mineral and bone metabolism during pregnancy, lactation, and fetal development. Excess PTHrP can also be produced by the placenta or the breasts during pregnancy, or by the breasts during lactation, and in both situations it can lead to hypercalcemia and other clinical features that are indistinguishable from HHM. The highest concentrations of PTHrP are found in milk, and recent evidence indicates that milk-based PTHrP may reduce mineral accretion by the newborn skeleton, but whether it does this through local actions in the neonatal gut or after absorption into the neonatal circulation is unknown.

PTHrP Overexpression Increases Sensitivity of Breast Cancer Cells to Apo2L/TRAIL

Parathyroid hormone-related protein (PTHrP) is a key component in breast development and breast tumour biology. PTHrP has been discovered as a causative agent of hypercalcaemia of malignancy and is also one of the main factors implicated in breast cancer mediated osteolysis. Clinical studies have determined that PTHrP expression by primary breast cancers was an independent predictor of improved prognosis. Furthermore, PTHrP has been demonstrated to cause tumour cell death both in vitro and in vivo. Apo2L/TRAIL is a promising new anti-cancer agent, due to its ability to selectively induce apoptosis in cancer cells whilst sparing most normal cells. However, some cancer cells are resistant to Apo2L/TRAIL-induced apoptosis thus limiting its therapeutic efficacy. The effects of PTHrP on cell death signalling pathways initiated by Apo2L/TRAIL were investigated in breast cancer cells. Expression of PTHrP in Apo2L/TRAIL resistant cell line MCF-7 sensitised these cells to Apo2L/TRAIL-induced apoptosis. The actions of PTHrP resulted from intracellular effects, since exogenous treatment of PTHrP had no effect on Apo2L/TRAIL-induced apoptosis. Apo2L/TRAIL-induced apoptosis in PTHrP expressing cells occurred through the activation of caspase-10 resulting in caspase-9 activation and induction of apoptosis through the effector caspases, caspase-6 and -7. PTHrP increased cell surface expression of Apo2L/TRAIL death receptors, TRAIL-R1 and TRAIL-R2. Antagonistic antibodies against the death receptors demonstrated that Apo2L/TRAIL mediated its apoptotic signals through activation of the TRAIL-R2 in PTHrP expressing breast cancer cells. These studies reveal a novel role for PTHrP with Apo2L/TRAIL that maybe important for future diagnosis and treatment of breast cancer.