Search

Introduction: Receptor activity-modifying proteins (RAMPs) are known to modulate the pharmacology and function of several G-protein-coupled receptors (GPCRs), including the parathyroid hormone 1 receptor (PTH1R). However, the precise effects of different RAMPs on PTH1R signalling and trafficking remain poorly understood. This study investigated the impact of RAMP2 and RAMP3 on PTH1R function using a range of PTH and PTH-related protein (PTHrP)-derived ligands. Methods: We employed FRET imaging to assess PTH1R interactions with RAMPs. Cell surface expression of PTH1R was evaluated in the presence of RAMPs. PTH1R-mediated cAMP accumulation, β-arrestin recruitment, and calcium signalling were measured in response to various ligands. Antibody-capture scintillation proximity assays were used to examine G-protein activation patterns. Results: PTH1R preferentially interacted with RAMP2 and, to a lesser extent, RAMP3, but not with RAMP1. RAMP3 co-expression reduced cell surface expression of PTH1R. RAMP2 significantly enhanced PTH1R-mediated signalling responses to PTH (1-34), PTHrP (1-34), PTH (1-84), and PTH (1-17) analogue ZP2307, while RAMP3 co-expression attenuated or abolished these responses. Full-length PTHrP analogues exhibited lower potency and efficacy than PTHrP (1-34) in activating PTH1R. RAMP2 increased the potency and/or efficacy of these analogues, whereas RAMP3 reduced these responses. RAMP2 differentially modulated G-protein activation by PTH1R in a ligand-dependent manner, with PTH (1-34) and PTHrP (1-34) inducing distinct patterns of G-protein subtype activation. Discussion: These findings highlight the complex role of RAMPs in regulating PTH1R signalling and trafficking, revealing differential effects of RAMP2 and RAMP3 on receptor function. The data suggest that targeting the PTH1R/RAMP2 complex may be a promising strategy for developing novel bone anabolic therapies by leveraging biased agonism and functional selectivity. Further research using physiologically relevant models is needed to elucidate the therapeutic potential of this approach. [ABSTRACT FROM AUTHOR]

Heterotopic ossification (HO) is a pathological process that generates ectopic bone in soft tissues. Hedgehog signaling (Hh signaling) is a signaling pathway that plays an important role in embryonic development and involves three ligands: sonic hedgehog (Shh), Indian hedgehog (Ihh) and desert hedgehog (Dhh). Hh signaling also has an important role in skeletal development. This paper discusses the effects of Hh signaling on the process of HO formation and describes several signaling molecules that are involved in Hh-mediated processes: parathyroid Hormone-Related Protein (PTHrP) and Fkbp10 mediate the expression of Hh during chondrogenesic differentiation. Extracellular signal-regulated kinase (ERK), GNAs and Yes-Associated Protein (YAP) interact with Hh signaling to play a role in osteogenic differentiation. Runt-Related Transcription Factor 2 (Runx2), Mohawk gene (Mkx) and bone morphogenetic protein (BMP) mediate Hh signaling during both chondrogenic and osteogenic differentiation. This paper also discusses possible therapeutic options for HO, lists several Hh inhibitors and explores whether they could serve as emerging targets for the treatment of HO. [ABSTRACT FROM AUTHOR]

Background: The main clinical features of pseudohypoparathyroidism (PHP)/inactivating parathyroid hormone/parathyroid hormone-related protein signaling disorders (iPPSD), including parathyroid hormone (PTH) resistance, brachydactyly and short stature, develop during middle and late childhood. Very few studies have addressed hearing loss in PHP/iPPSD patients, and these studies have yielded widely divergent conclusions. The aim of our study was to assess hearing and determine the predictive factors of hearing loss in patients with PHP/iPPSD. Methods: Our retrospective cohort study was conducted between March 2019 and May 2020 in the Otolaryngology Department and the calcium phosphate reference center for rare diseases in Bicêtre Paris-Saclay Hospital, France. We retrospectively collected data from patients with PHP/iPPSDs (age, sex, genetic mutations, height, body mass index (BMI), PTH resistance, presence or absence of ectopic ossifications and brachydactyly). All patients underwent auditory investigations, including tonal and vocal audiometry. The primary outcome was the pure tone average (PTA). The PTA was compared with the norm according to the International Organization for Standardization. Hearing loss was defined as a PTA ≥ 20 db. Results: The median age of the patients was 15.6 years [9.5, 28.5]. Thirty-six patients were diagnosed with iPPSD2, and eight were diagnosed with iPPSD3. Twenty-six of them (59%) were female. Hearing impairment was confirmed in 17 patients (39%). The mean PTA and the mean SRT of the deaf ears were 40 ± 26 db and 31 ± 14 db. The mean difference in the PTA between the patients and the normal controls was 11.4 db (p = 0.00002). Short stature and the presence of ectopic ossifications were two significant predictive factors of hearing loss (p = 0.009 and p = 0.03, respectively). Sex, BMI, PTH resistance, mutation category and brachydactyly were not associated with an increased risk of hearing loss (p = 0.19, p = 0.41, p = 0.13, p = 0.50, p = 0.19, respectively). Conclusion: Our study confirmed the frequency of hearing loss in patients with PHP/iPPSD disease (prevalence = 39%). A diagnosis of PHP/iPPSD should trigger auditory investigations and follow-up, especially when short stature and/or ectopic ossifications are present. [ABSTRACT FROM AUTHOR]

Coenzyme management is important for homeostasis of the pool of active metabolic enzymes. The coenzyme pyridoxal 5′-phosphate (PLP) is involved in diverse enzyme reactions including amino acid and hormone metabolism. Regulatory proteins that contribute to PLP homeostasis remain to be explored in plants. Here, we demonstrate the importance of proteins annotated as PLP homeostasis proteins (PLPHPs) for controlling PLP in Arabidopsis (Arabidopsis thaliana). A systematic analysis indicates that while most organisms across kingdoms have a single PLPHP homolog, Angiosperms have two. PLPHPs from Arabidopsis bind PLP and exist as monomers, in contrast to reported PLP-dependent enzymes, which exist as multimers. Disrupting the function of both PLPHP homologs perturbs vitamin B6 (pyridoxine) content, inducing a PLP deficit accompanied by light hypersensitive root growth, unlike PLP biosynthesis mutants. Micrografting studies show that the PLP deficit can be relieved distally between shoots and roots. Chemical treatments probing PLP-dependent reactions, notably those for auxin and ethylene, provide evidence that PLPHPs function in the dynamic management of PLP. Assays in vitro show that Arabidopsis PLPHP can coordinate PLP transfer and withdrawal from other enzymes. This study thus expands our knowledge of vitamin B6 biology and highlights the importance of PLP coenzyme homeostasis in plants. Pyridoxal phosphate homeostasis proteins contribute to vitamin B6 (pyridoxine) homeostasis, likely acting as a rheostat in adaptive responses involving the coenzyme pyridoxal 5′-phosphate. [ABSTRACT FROM AUTHOR]

Simple Summary: Cholangiocarcinomas, malignant tumours originating from the biliary epithelium, have had an increasing incidence during recent decades; thus, awareness represents the key operating factor nowadays. Our purpose was to overview the tumour field following the constellation of the risk factors and the paraneoplastic syndromes, emphasizing the endocrine features amid the entire multidisciplinary panel. The hormonal burden is reflected by complex interplays such as the galanin system, exposure to sex hormone therapy, interferences with vitamin D system, etc., while humoral hypercalcaemia of malignancy, although rare, has been reported due to parathyroid hormone-related protein over-production in addition to other elements such a fibroblast growth factor receptor-positive or even procalcitonin-positive tumour. The level of endocrine evidence across clinical trials remains far from generous. Further applications such as emergent hormonal biomarkers are expected for daily practice. Cholangiocarcinomas (CCAs), a heterogeneous group of challenging malignant tumours which originate from the biliary epithelium, are associated with an alarming increasing incidence during recent decades that varies between different regions of the globe. Thus, awareness represents the key operating factor. Our purpose was to overview the field of CCAs following a double perspective: the constellation of the risk factors, and the presence of the paraneoplastic syndromes, emphasizing the endocrine features amid the entire multidisciplinary panel. This is a narrative review. A PubMed-based search of English-language original articles offered the basis of this comprehensive approach. Multiple risk factors underlying different levels of statistical evidence have been listed such as chronic biliary diseases and liver conditions, inflammatory bowel disease, parasitic infections (e.g., Opisthorchis viverrini, Clonorchis sinensis), lifestyle influence (e.g., alcohol, smoking), environmental exposure (e.g., thorotrast, asbestos), and certain genetic and epigenetic interplays. With regard to the endocrine panel, a heterogeneous spectrum should be taken into consideration: non-alcoholic fatty liver disease, obesity, type 2 diabetes mellitus, and potential connections with vitamin D status, glucagon-like peptide 1 receptor, or the galanin system, respectively, with exposure to sex hormone therapy. Amid the numerous dermatologic, hematologic, renal, and neurologic paraneoplastic manifestations in CCAs, the endocrine panel is less described. Humoral hypercalcaemia of malignancy stands as the most frequent humoral paraneoplastic syndrome in CCAs, despite being exceptional when compared to other paraneoplastic (non-endocrine) manifestations and to its reported frequency in other (non-CCAs) cancers (it accompanies 20–30% of all cancers). It represents a poor prognosis marker in CCA; it may be episodic once the tumour relapses. In addition to the therapy that targets the originating malignancy, hypercalcaemia requires the administration of bisphosphonates (e.g., intravenous zoledronic acid) or denosumab. Early detection firstly helps the general wellbeing of a patient due to a prompt medical control of high serum calcium and it also provides a fine biomarker of disease status in selected cases that harbour the capacity of PTHrP secretion. The exact molecular biology and genetic configuration of CCAs that display such endocrine traits is still an open matter, but humoral hypercalcaemia adds to the overall disease burden. [ABSTRACT FROM AUTHOR]

We present a case of a PTH-related peptide (PTH-rp) producing uterine myoma, leading to hypercalcemia in pregnancy. Our patient presented with dehydration, hypotension, delirium, and malnutrition. Due to a serum calcium level of 17.9 mg/dL (4.48 mmol/L) (reference range 8.8-11.2 mg/dL; 2.20-2.80 mmol/L), prompt treatment with hydration and calcitonin was initiated. The patient went into labor before we could consider other treatment options. Although uncommon in pregnancy, it is of great importance to identify hypercalcemia since it is related to a high risk of maternal and neonatal morbidity and mortality. Because bisphosphonates are contraindicated in pregnancy, hydration and calcitonin are the cornerstones of treatment for PTH-rp-induced hypercalcemia. [ABSTRACT FROM AUTHOR]

A 5-year-old, entire, female Greenland dog was presented with polyuria and polydipsia. A mildly increased circulating concentration of ionised calcium, mild non-regenerative anaemia, mild hypercholesterolemia and mild increases in liver enzyme activity were detected. Parathyroid hormone, plasma parathyroid hormone-related protein and vitamin D were analysed in a blood sample, with all results below the lower limit of the reference range. Further investigation with abdominal ultrasonography, fine-needle aspiration for cytology of the liver and spleen, thoracic radiography, adrenocorticotropic hormone-stimulation and serum protein electrophoresis could not detect any disease. During the next months, the dog developed coat changes that clinically corresponded to an endocrinopathy. Analysis of thyroxine and thyroid-stimulating hormone was performed. Thyroxine was less than 6 nmol/L and thyroid-stimulating hormone was 1.5 µg/L, which indicated primary hypothyroidism. Treatment with l-thyroxine resulted in normalisation of the hypercalcaemia. Moreover, the polyuria and alopecia resolved. [ABSTRACT FROM AUTHOR]

Bacterial lipopolysaccharides belong to the group of pathogen-associated molecular patterns such as alarmins. They can cause various dysfunctions of the cardiovascular system, including arrhythmia, myocardial hypertrophy, myocarditis, and heart failure. The damaging effect of lipopolysaccharides on the myocardium can be a result of their direct action or ensured by uncontrolled secretion of endogenous alarmins and cytotoxic shock. Lipopolysaccharides are perceived by specific caspases of host cells and activate the release of interleukins, and in maximum stimulation they lead to necrosis and/or pyroptosis of cells. The mechanism of the action of bacterial lipopolysaccharide on the functional activity of the heart was studied in vitro using an isolated frog heart model. By the method of pharmacological blockade, the participation of calcium and potassium channels, phosphodiesterase and Na+-K+-ATPase in the mechanism of the lipopolysaccharide influence on the inotropic and chronotropic activity of the heart was revealed. In our experiments, we observed a dose-dependent negative effect of lipopolysaccharide on the inotropic and chronotropic functions of isolated frog heart, as well as a significant reduction in its viability. It is assumed that the mechanism of the action of lipopolysaccharide on the heart involves calcium and potassium ions, Na+-K+-ATPase and cAMP. The study investigated the role of the calcium-regulating hormonal system (including parathyroid hormone, parathyroid hormone-related protein, calcitonin, and vitamin D3) in preventing disturbances in the functional parameters of the isolated heart induced by bacterial lipopolysaccharide. The protective role of these hormones in preserving the pacemaker and contractile functions of the heart under the influence of bacterial lipopolysaccharide has been shown. A particularly significant effect is exerted by vitamin D3, parathyroid hormone and parathyroid hormone-related protein, which maintain the functional activity of the isolated heart for a long time. [ABSTRACT FROM AUTHOR]

We describe a case of mandibular gingival carcinoma with hypercalcaemia and leukocytosis caused by tumour-derived parathyroid hormone-related protein (PTHrP) and granulocyte colony-stimulating factor (G-CSF). A 54-year-old man presented to our Department of Oral and Maxillofacial Surgery with a chief complaint of a left-sided mandibular gingival ulcer. A 42 mm × 20 mm sized ulcer was found on the left lower molar gingiva. Squamous cell carcinoma was pathologically diagnosed. The patient underwent a hemimandibulectomy, left-sided radical neck dissection, plate reconstruction, pectoralis major musculocutaneous flap reconstruction, and tracheostomy under general anaesthesia. Pathologically, two metastatic lymph nodes were identified. Residual tumour was suspected at the resection margins. Eight weeks after surgery, the patient started postoperative concurrent chemoradiotherapy (CCRT). Two weeks after CCRT, the patient developed hypercalcaemia. Serum levels of PTHrP and G-CSF increased in parallel with the progression of hypercalcaemia and leukocytosis. Immunohistochemical analysis of the surgical specimen showed positivity for G-CSF. Based on these clinical and pathological findings, the patient was diagnosed with hypercalcaemia and leukocytosis associated with malignancy and was treated with denosumab. Irradiation was terminated at 50 Gy because CT showed rapid disease progression. Chemotherapy was initiated, however, four weeks after the start of chemotherapy, a CT scan showed increased metastases and pleural dissemination. Therefore, chemotherapy was discontinued. One week after the chemotherapy was discontinued, the patient died of respiratory failure. [ABSTRACT FROM AUTHOR]

Introduction: Lung adenocarcinoma with parathyroid hormone (PTH)-related hypercalcemia is uncommon. Case Presentation: A 69-year-old man was admitted to our hospital due to anorexia and fatigue. Serum calcium (15.0 mg/dL) and carcinoembryonic antigen (361.7 ng/mL) were extremely high, and PTH-related protein (PTH-rP) also elevated (16.7 pmol/L). Systemic computed tomography revealed multiple enlarged lymph nodes and disseminated peritoneal nodules, with irregularly shaped nodules in the upper lobe in the left lung. Ultrasound-guided biopsy from the axillary lymph node revealed adenocarcinoma. Immunohistological staining showed the tumor cells to be positive for cytokeratin 7 and PTH-rP and negative for cytokeratin 20 and thyroid transcription factor-1. Although the primary origin remains undetermined despite detailed examinations, possible primary tumor was considered to be lung adenocarcinoma in the present case. The serum calcium level was reduced by denosumab, but the patient died 20 days after admission. Conclusion: The present case demonstrated the importance of considering oncological emergency, such as hypercalcemia and/or PTH-rP-producing hypercalcemia, in patients with adenocarcinoma. [ABSTRACT FROM AUTHOR]

Primary failure of eruption (PFE) is a rare disorder that is characterized by the inability of a molar tooth/teeth to erupt to the occlusal plane or to normally react to orthodontic force. This condition is related to hereditary factors and has been extensively researched over many years. However, the etiological mechanisms of pathogenesis are still not fully understood. Evidence from studies on PFE cases has shown that PFE patients may carry parathyroid hormone 1 receptor (PTH1R) gene mutations, and genetic detection can be used to diagnose PFE at an early stage. PTH1R variants can lead to altered protein structure, impaired protein function, and abnormal biological activities of the cells, which may ultimately impact the behavior of teeth, as observed in PFE. Dental follicle cells play a critical role in tooth eruption and root development and are regulated by parathyroid hormone-related peptide (PTHrP)–PTH1R signaling in their differentiation and other activities. PTHrP–PTH1R signaling also regulates the activity of osteoblasts, osteoclasts and odontoclasts during tooth development and eruption. When interference occurs in the PTHrP–PTH1R signaling pathway, the normal function of dental follicles and bone remodeling are impaired. This review provides an overview of PTH1R variants and their correlation with PFE, and highlights that a disruption of PTHrP–PTH1R signaling impairs the normal process of tooth development and eruption, thus providing insight into the underlying mechanisms related to PTH1R and its role in driving PFE. [ABSTRACT FROM AUTHOR]

Maternal Parathyroid Hormone-related Protein (PTHrP) is involved in the placental transport of calcium. Autonomous overproduction of PTHrP is a rare cause of hypercalcemia in pregnancy. Prior cases of PTHrP-induced hypercalcemia in pregnancy have been managed with either dopamine agonists, fetal delivery, termination of pregnancy, or mastectomy. However, PTHrP level normalization following mastectomy has not previously been documented. Herein, we present a 39-year-old female hospitalized at 19 weeks of gestation for acute encephalopathy due to PTHrP induced hypercalcemic crisis (calcium 15.8 mg/dL, PTHrp 46.5 pmol/L [normal 0-3.4]). Mammary hyperplasia resulting in gigantomastia significantly impaired her ability to ambulate and perform activities of daily living. She remained hypercalcemic during hospitalization despite aggressive hydration, calcitonin, and 2 weeks of dopamine agonist treatment. Bisphosphonate therapy was not administered due to pregnancy and potential effects on the fetus. Our patient underwent bilateral mastectomy along with excision of a large axillary mass. The pathology of all three specimens revealed mammary stromal hyperplasia. PTHrP was undetectable on post-op day 2 and calcium normalized by post-op day 3. At discharge, she was able to ambulate independently. To our knowledge, this is the first reported case of PTHrP induced hypercalcemia related to gigantomastia, documenting resolution of hypercalcemia, and PTHrP levels following mastectomy. Mastectomy is a potential option in the second trimester for pregnant patients with PTHrP induced severe hypercalcemia due to gigantomastia, refractory to treatment with dopamine agonist therapy. Lay Summary: Parathyroid Hormone-related Protein (PTHrP) is important for transportation of calcium during pregnancy, facilitating fetal skeleton formation. Rarely, excess production of PTHrP can cause critically elevated calcium levels in pregnancy. We present a 39-yr-old female hospitalized at 19 wk of gestation for altered mental status, due to PTHrP-induced hypercalcemic crisis. She demonstrated profound breast enlargement and a left axillary mass, impairing her ability to walk and work. Despite aggressive hydration, and medical treatment targeted to lower calcium, her calcium remained significantly elevated. She underwent surgical removal of both breasts and excision of the axillary mass which each demonstrated mammary stromal hyperplasia. PTHrP levels became undetectable, and calcium quickly normalized. To our knowledge, this is the first reported documentation of resolution of hypercalcemia and PTHrP levels following surgical resection of the excess breast enlargement during pregnancy. Graphical Abstract [ABSTRACT FROM AUTHOR]

Dysregulated overproduction of parathyroid hormone (PTH), the prototypic calciotropic hormone, is a common endocrine disorder with the greatest prevalence in adult women. Hyperparathyroidism conveys increased risk for long-term cardiovascular (CV) morbidity and mortality independent of serum calcium levels. Primary hyperparathyroidism (pHPT) impairs normal arterial vasorelaxation and blood flow in response to physiological demands of the heart and kidneys. The PTH 1 receptor (PTH1R), shared by PTH and PTH-related protein, is highly expressed and biologically active in the CV system in addition to bone and kidney. Marked differences exist in the CV response to acute vs chronic PTH exposure, mediated in part via rapid tachyphylaxis to vascular PTH1R activation that normally improves arterial blood flow. A better understanding of vascular PTH/PTH1R signaling provides novel targets for therapeutic intervention CV disease including arteriosclerosis, CV fibrosis, and heart failure. Validated biomarkers are needed to establish the healthy 'set point' for CV PTH1R signaling tone to better guide the management of patients with pHPT or secondary hyperparathyroidism. Primary hyperparathyroidism (pHPT) afflicts our aging population with an incidence approaching 50 per 100 000 patient-years at a female:male ratio of ~3:1. Decisions surrounding surgical management are currently driven by age, hypercalcemia severity, presence of osteoporosis, renal insufficiency, or hypercalciuria with or without nephrolithiasis. Cardiovascular (CV) disease (CVD) is not systematically considered. This is notable since the parathyroid hormone (PTH) 1 receptor (PTH1R) is biologically active in the vasculature, and adjusted CV mortality risk is increased almost threefold in individuals with pHPT who do not meet contemporary recommendations for surgical cure. We provide an overview of epidemiology, pharmacology, and physiology that highlights the need to: (i) identify biomarkers that establish a healthy 'set point' for CV PTH1R signaling tone; (ii) better understand the pharmacokinetic–pharmacodynamic (PK-PD) relationships of PTH1R ligands in CV homeostasis; and (iii) incorporate CVD risk assessment into the management of hyperparathyroidism. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate changes in the concentration of N-terminal type I collagen extension pro-peptide (PINP), tartrate-resistant acid phosphatase (TRAcP), and parathyroid hormone-related protein (PTHrP) in saliva during orthodontic treatment in order to evaluate whether changes in bone turnover marker (BTM) concentration can help highlight the effects of orthodontic mechanical loading in the absence of clinical evidence of tooth movement in terms of tooth movement. Saliva samples from 25 apparently healthy young subjects (10 females and 15 males) were collected using Salivette® (Sarstedt) with cotton swabs and the concentrations of PTHrP, TRAcP 5b, and PINP were analyzed at time 0 (T1), 25 days (T2), and at 45 days (T3). Differences in the median value of biomarker levels between baseline T1 and follow-up of the different groups (T2 and T3) were assessed using the non-parametric Mann–Whitney U test. Trough concentrations of P1NP, PTHrP, and TRAcP were 0.80 µg/L, 0.21 ng/mL, and 0.90 U/L above the method LOD. The non-parametric Mann–Whitney U test confirmed a statistically significant difference in T1 versus concentrations of T2 and T3. All subjects evaluated had a statistically significant difference between T1 vs. T3. when compared with the specific critical difference (RCV) for the analyte The results obtained demonstrate that the evaluation of BTM changes in saliva can help the evaluation of orthodontic procedures and the monitoring of biomechanical therapy. [ABSTRACT FROM AUTHOR]

Calcium plays central roles in numerous biological processes, thereby, its levels in the blood are under strict control to maintain homeostatic balance and enable the proper functioning of living organisms. The regulatory mechanisms ensuring this balance can be affected by pathologies such as cancer, and as a result, hyper- or hypocalcemia can occur. These states, characterized by elevated or decreased calcium blood levels, respectively, have a significant effect on general homeostasis. This article focuses on a particular form of calcium metabolism disorder, which is hypercalcemia in neoplasms. It also constitutes a summary of the current knowledge regarding the diagnosis of hypercalcemia and its management. Hypercalcemia of malignancy is estimated to affect over 40% of cancer patients and can be associated with both solid and blood cancers. Elevated calcium levels can be an indicator of developing cancer. The main mechanism of hypercalcemia development in tumors appears to be excessive production of parathyroid hormone-related peptides. Among the known treatment methods, bisphosphonates, calcitonin, steroids, and denosumab should be mentioned, but ongoing research promotes progress in pharmacotherapy. Given the rising global cancer prevalence, the problem of hypercalcemia is of high importance and requires attention. [ABSTRACT FROM AUTHOR]

Teriparatide, an osteoanabolic agent, is a biosynthetic analogue of the 1-34 amino acids of human parathyroid hormone (PTH) used for the treatment of osteoporosis. It is typically well-tolerated; common side effects include headaches, arthralgias, nausea, and dizziness. In this report, we present a case of gynecomastia occurring shortly after initiating teriparatide therapy, associated with nipple sensitivity and breast tenderness. Secondary workup for various causes of gynecomastia was unremarkable. Finally, a decision was made to discontinue teriparatide due to the patient's concerns. The nipple sensitivity started improving shortly afterward, with complete resolution of gynecomastia 4 months later. Although this unusual side effect has been reported as a possibility in postmarketing studies, a chronological report on the occurrence of teriparatide-induced gynecomastia and its complete resolution after discontinuing teriparatide has not yet been published in the literature. [ABSTRACT FROM AUTHOR]

Breast cancer bone metastases (BMET) are incurable, primarily osteolytic, and occur most commonly in estrogen receptor-α positive (ER+) breast cancer. ER+ human breast cancer BMET modeling in mice has demonstrated an estrogen (E2)-dependent increase in tumor-associated osteolysis and bone-resorbing osteoclasts, independent of estrogenic effects on tumor proliferation or bone turnover, suggesting a possible mechanistic link between tumoral ERα-driven osteolysis and ER+ bone progression. To explore this question, inducible secretion of the osteolytic factor, parathyroid hormone–related protein (PTHrP), was utilized as an in vitro screening bioassay to query the osteolytic potential of estrogen receptor- and signaling pathway–specific ligands in BMET-forming ER+ human breast cancer cells expressing ERα, ERß, and G protein–coupled ER. After identifying genomic ERα signaling, also responsibility for estrogen's proliferative effects, as necessary and sufficient for osteolytic PTHrP secretion, in vivo effects of a genomic-only ER agonist, estetrol (E4), on osteolytic ER+ BMET progression were examined. Surprisingly, while pharmacologic effects of E4 on estrogen-dependent tissues, including bone, were evident, E4 did not support osteolytic BMET progression (vs robust E2 effects), suggesting an important role for nongenomic ER signaling in ER+ metastatic progression at this site. Because bone effects of E4 did not completely recapitulate those of E2, the relative importance of nongenomic ER signaling in tumor vs bone cannot be ascertained here. Nonetheless, these intriguing findings suggest that targeted manipulation of estrogen signaling to mitigate ER+ metastatic progression in bone may require a nuanced approach, considering genomic and nongenomic effects of ER signaling on both sides of the tumor/bone interface. [ABSTRACT FROM AUTHOR]

The treatment of parathyroid hormone-related protein (PTHrP)-mediated hypercalcemia of malignancy includes treating the malignancy, intravenous fluids, and anti-resorptive therapies such as zoledronic acid or denosumab. PTHrP-mediated hypercalcemia has been reported in benign conditions such as systemic lupus erythematous (SLE) and sarcoidosis and appears to be responsive to glucocorticoids. We report a case of PTHrP-induced hypercalcemia due to a malignancy-low grade fibromyxoid sarcoma-that responded to glucocorticoid treatment. This is the first report of glucocorticoids controlling PTHrP-mediated hypercalcemia of malignancy. Immunohistochemistry of the surgical pathology localized PTHrP staining to the vascular endothelial cells within the tumor. Further studies are needed to elucidate the mechanism of glucocorticoid action in the treatment of PTHrP-mediated hypercalcemia of malignancy.

BackgroundIn the acute setting, PTH-independent hypercalcemia is typically treated with anti-resorptive agents such as zoledronic acid or denosumab. When these agents are no longer able to control hypercalcemia, several case reports have shown the utility of cinacalcet. However, it is not known if cinacalcet can be effective in patients naïve to anti-resorptive therapy or how cinacalcet ameliorates the hypercalcemia.Case presentationA 47-year-old male with a history of alcohol-induced cirrhosis was admitted for left cheek bleeding and swelling from an infiltrative squamous cell carcinoma of the oral cavity. On admission, he was found to have an elevated albumin-corrected serum calcium of 13.6 mg/dL, a serum phosphorus of 2.2 mg/dL and an intact PTH of 6 pg/mL (normal 18-90) with a PTHrP of 8.1 pmol/L (normal

IntroductionReceptor activity-modifying proteins (RAMPs) are known to modulate the pharmacology and function of several G-protein-coupled receptors (GPCRs), including the parathyroid hormone 1 receptor (PTH1R). However, the precise effects of different RAMPs on PTH1R signalling and trafficking remain poorly understood. This study investigated the impact of RAMP2 and RAMP3 on PTH1R function using a range of PTH and PTH-related protein (PTHrP)-derived ligands.MethodsWe employed FRET imaging to assess PTH1R interactions with RAMPs. Cell surface expression of PTH1R was evaluated in the presence of RAMPs. PTH1R-mediated cAMP accumulation, β-arrestin recruitment, and calcium signalling were measured in response to various ligands. Antibody-capture scintillation proximity assays were used to examine G-protein activation patterns.ResultsPTH1R preferentially interacted with RAMP2 and, to a lesser extent, RAMP3, but not with RAMP1. RAMP3 co-expression reduced cell surface expression of PTH1R. RAMP2 significantly enhanced PTH1R-mediated signalling responses to PTH (1-34), PTHrP (1-34), PTH (1-84), and PTH (1-17) analogue ZP2307, while RAMP3 co-expression attenuated or abolished these responses. Full-length PTHrP analogues exhibited lower potency and efficacy than PTHrP (1-34) in activating PTH1R. RAMP2 increased the potency and/or efficacy of these analogues, whereas RAMP3 reduced these responses. RAMP2 differentially modulated G-protein activation by PTH1R in a ligand-dependent manner, with PTH (1-34) and PTHrP (1-34) inducing distinct patterns of G-protein subtype activation.DiscussionThese findings highlight the complex role of RAMPs in regulating PTH1R signalling and trafficking, revealing differential effects of RAMP2 and RAMP3 on receptor function. The data suggest that targeting the PTH1R/RAMP2 complex may be a promising strategy for developing novel bone anabolic therapies by leveraging biased agonism and functional selectivity. Further research using physiologically relevant models is needed to elucidate the therapeutic potential of this approach.

Parathyroid hormone-related protein (PTHrP) released from detrusor smooth muscle (DSM) cells upon bladder distension attenuates spontaneous phasic contractions (SPCs) in DSM and associated afferent firing to facilitate urine storage. Here, we investigate the mechanisms underlying PTHrP-induced inhibition of SPCs, focusing on large-conductance Ca2+-activated K+ channels (BK channels) that play a central role in stabilizing DSM excitability. Perforated patch-clamp techniques were applied to DSM cells of the rat bladder dispersed using collagenase. Isometric tension changes were recorded from DSM strips, while intracellular Ca2+ dynamics were visualized using Cal520 AM -loaded DSM bundles. DSM cells developed spontaneous transient outward potassium currents (STOCs) arising from the opening of BK channels. PTHrP (10 nM) increased the frequency of STOCs without affecting their amplitude at a holding potential of − 30 mV but not − 40 mV. PTHrP enlarged depolarization-induced, BK-mediated outward currents at membrane potentials positive to + 20 mV in a manner sensitive to iberiotoxin (100 nM), the BK channel blocker. The PTHrP-induced increases in BK currents were also prevented by inhibitors of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) (CPA 10 µM), L-type voltage-dependent Ca2+ channel (LVDCC) (nifedipine 3 µM) or adenylyl cyclase (SQ22536 100 µM). PTHrP had no effect on depolarization-induced LVDCC currents. PTHrP suppressed and slowed SPCs in an iberiotoxin (100 nM)-sensitive manner. PTHrP also reduced the number of Ca2+ spikes during each burst of spontaneous Ca2+ transients. In conclusion, PTHrP accelerates STOCs discharge presumably by facilitating SR Ca2+ release which prematurely terminates Ca2+ transient bursts resulting in the attenuation of SPCs. [ABSTRACT FROM AUTHOR]

In infants, hypercalcemia from elevated parathyroid hormone-related protein (PTHrP) is rare, often signaling neoplasm or renal or urinary anomalies. We report an infant who presented with failure to thrive and hypercalcemia at 10 months old, with initial evaluation showing elevated PTHrP of unclear etiology with imaging negative for neoplasm and no structural anomalies of the kidneys or ureters on ultrasound. Within 6 months of presentation, the patient developed nephrotic syndrome and by 2 years had progressed to end-stage kidney disease, necessitating kidney transplantation. Genetic testing was inconclusive but suggested congenital nephrotic syndrome. While reports of hypercalcemia secondary to elevated PTHrP exist in children with known structural renal anomalies, this is the first to demonstrate hypercalcemia and PTHrP elevation before detection of renal abnormalities. Experimental models have suggested a role for increased PTHrP expression in renal cells following acute kidney injury from nephrotic syndrome, and clinically detectable PTHrP levels may indicate progression of renal injury. We suggest monitoring of renal function for early detection of nephrotic syndrome in infants and children with elevated PTHrP who otherwise lack anatomical renal anomalies or detectable malignancies. [ABSTRACT FROM AUTHOR]

This article discusses a case of a large perianal mass in a 7-year-old male castrated mixed breed dog. The mass was diagnosed as an apocrine gland anal sac adenocarcinoma (AGASACA) with atypical mesenchymal cells. The dog exhibited symptoms such as decreased appetite and activity level, and laboratory tests revealed hypercalcemia and other abnormalities. The presence of a large mesenchymal cell component in the tumor was an atypical finding, suggesting a possible epithelial to mesenchymal transition (EMT). The article also discusses the immunohistochemistry results and the potential implications of the findings. [Extracted from the article]

Background: In vitro chondrogenesis of mesenchymal stromal cells (MSCs) driven by the essential chondro-inducer transforming growth factor (TGF)-β is instable and yields undesired hypertrophic cartilage predisposed to bone formation in vivo. TGF-β can non-canonically activate bone morphogenetic protein-associated ALK1/2/3 receptors. These have been accused of driving hypertrophic MSC misdifferentiation, but data remained conflicting. We here tested the antihypertrophic capacity of two highly specific ALK1/2/3 inhibitors – compound A (CompA) and LDN-212854 (LDN21) – in order to reveal potential prohypertrophic contributions of these BMP/non-canonical TGF-β receptors during MSC in vitro chondrogenesis. Methods: Standard chondrogenic pellet cultures of human bone marrow-derived MSCs were treated with TGF-β and CompA (500 nM) or LDN21 (500 nM). Daily 6-hour pulses of parathyroid hormone-related peptide (PTHrP[1–34], 2.5 nM, from day 7) served as potent antihypertrophic control treatment. Day 28 samples were subcutaneously implanted into immunodeficient mice. Results: All groups underwent strong chondrogenesis, but GAG/DNA deposition and ACAN expression were slightly but significantly reduced by ALK inhibition compared to solvent controls along with a mild decrease of the hypertrophy markers IHH-, SPP1-mRNA, and Alkaline phosphatase (ALP) activity. When corrected for the degree of chondrogenesis (COL2A1 expression), only pulsed PTHrP but not ALK1/2/3 inhibition qualified as antihypertrophic treatment. In vivo, all subcutaneous cartilaginous implants mineralized within 8 weeks, but PTHrP pretreated samples formed less bone and attracted significantly less haematopoietic marrow than ALK1/2/3 inhibitor groups. Conclusions: Overall, our data show that BMP-ALK1/2/3 inhibition cannot program mesenchymal stromal cells toward stable chondrogenesis. BMP-ALK1/2/3 signalling is no driver of hypertrophic MSC misdifferentiation and BMP receptor induction is not an adverse prohypertrophic side effect of TGF-β that leads to endochondral MSC misdifferentiation. Instead, the prohypertrophic network comprises misregulated PTHrP/hedgehog signalling and WNT activity, and a potential contribution of TGF-β-ALK4/5-mediated SMAD1/5/9 signalling should be further investigated to decide about its postulated prohypertrophic activity. This will help to successfully engineer cartilage replacement tissues from MSCs in vitro and translate these into clinical cartilage regenerative therapies. [ABSTRACT FROM AUTHOR]

Ameloblastoma is a rare odontogenic tumor which may be complicated by hypercalcemia in advanced disease. Tumoral parathyroid hormone-related peptide (PTHrP) production and local osteolysis from paracrine factors have been proposed as mechanisms. Mitogen-activated protein kinase (MAPK) inhibitors have been successfully used in ameloblastomas with BRAF V600E mutation to reduce symptoms and decrease tumor burden. Serum calcium has been observed to normalize following treatment with MAPK inhibitors; however, the response of PTHrP and markers of bone turnover has not been reported. We describe a case of a 55-year-old female with PTHrP-mediated hypercalcemia secondary to BRAF V600E-positive ameloblastoma with pulmonary metastases. Following treatment with dabrafenib and trametinib, the patient experienced the regression of pulmonary lesions and normalization of serum calcium, PTHrP, and markers of bone turnover. Tissue samples of ameloblastoma carrying BRAF V600E mutation are more likely to express PTHrP than tissue samples carrying wild-type BRAF. In our case, resolution of PTHrP-mediated hypercalcemia following initiation of BRAF/MEK inhibition provides additional evidence that the MAPK pathway contributes to PTHrP synthesis. It also raises the question of whether MAPK inhibitors would be effective in treating PTHrP-mediated hypercalcemia associated with other malignancies harboring BRAF V600E mutation. [ABSTRACT FROM AUTHOR]

Gouty arthritis results from monosodium urate (MSU) crystal deposition in joints, initiating (pro)-interleukin (IL)-1β maturation, inflammatory mediator release, and neutrophil infiltration, leading to joint swelling and pain. Parathyroid hormone-related protein (107–111) C-terminal peptide (osteostatin) has shown anti-inflammatory properties in osteoblasts and collagen-induced arthritis in mice, but its impact in gouty arthritis models remains unexplored. We investigated the effect of osteostatin on pyroptosis, inflammation, and oxidation in macrophages, as well as its role in the formation of calcium pyrophosphate dihydrate crystals and MSU-induced gouty arthritis in mice models. Osteostatin ameliorated pyroptosis induced by lipopolysaccharide and adenosine 5′-triphosphate (LPS + ATP) in mice peritoneal macrophages by reducing the expression of caspase-1, lactate dehydrogenase release, and IL-1β and IL-18 secretion. Additionally, IL-6 and tumor necrosis factor-α (TNF-α) were also decreased due to the reduced activation of the NF-κB pathway. Furthermore, osteostatin displayed antioxidant properties in LPS + ATP-stimulated macrophages, resulting in reduced production of mitochondrial and extracellular reactive oxygen species and enhanced Nrf2 translocation to the nuclei. In both models of gouty arthritis, osteostatin administration resulted in reduced pro-inflammatory cytokine production, decreased leukocyte migration, and reduced caspase-1 and NF-κB activation. These results highlight the potential of osteostatin as a therapeutic option for gouty arthritis. [ABSTRACT FROM AUTHOR]

This document provides abstracts of presentations by the winners of The Japanese Society of Pathology; Japan Pathology Award in 2024. The presentations cover a range of topics related to cancer pathology and gene expression. They discuss the importance of the tumor microenvironment, the impact of cancer-associated fibroblasts on cancer cell invasion, the subclassification of cancer-associated fibroblasts and their role in modifying drug sensitivity and the immune microenvironment, the regulatory mechanisms and alterations of gene expression in osteoclastogenesis and related diseases, and the mechanisms and risk assessment of chemical-induced cancer. The researchers have made significant contributions to our understanding of these topics, providing insights into the underlying mechanisms and helping assess human health risks. [Extracted from the article]

Introduction: Among the Palestinian population, lung cancer was the most common cause of death among cancer patients (22.8%) followed by prostate cancer (9.5%). Aim of the Work: The aims of this study were to examine the expression of prostate specific antigen (PSA) and parathyroid hormone-related protein (PTHrP) in prostatic adenocarcinoma. Materials and Methods: Fifty-eight prostatic tissue sections: 6 benign prostatic hyperplasia (BPH) and 52 prostatic carcinomas were stained with hematoxylin and eosin for grading identification. Moreover, tissue blocks were immunohistochemically stained for PSA and PTHrP using specific monoclonal antibodies, including anti-PSA and anti-PTHrP. Area and intensity of staining for PSA and PTHrP were quantitatively analyzed and correlated with the documented seven forms of Gleason scores. Results: Generally, PSA and PTHrP expressions were positive in all specimens. In those specimens with positive staining, the expression varied between cells. PSA expression was positively (P < 0.001) correlated to the expression of PTHrP among all investigated specimens. It is obvious that the area (μm2) of immunoexpressed PSA and PTHrP was positively (r = 0.274 and r = 0.474, P < 0.001) correlated with the various grades of prostate cancer. However, the intensity displayed a negative correlation (r = - 0.619 and r = - 0.359, P < 0.001) between the immunoexpressed PSA and PTHrP and the various grades of prostate cancer, respectively. Thereby, the immunoreactivity for PSA is related to PTHrP expression in prostatic tissue. Conclusion: The counteract behavior of area and intensity of expressed PSA and PTHrP has to be considered during diagnosis. This immunophenotypic characteristic should be focused on advanced scores of Gleason scores.. [ABSTRACT FROM AUTHOR]

Hypercalcemia is a common paraneoplastic syndrome. Malignancies cause hypercalcemia by various mechanisms. Usually a single mechanism underlies paraneoplastic hypercalcemia. Two simultaneous mechanisms associated with one malignancy, however, are occasionally encountered. Here a rare case is reported to describe simultaneous PTHrp- and calcitriol-mediated hypercalcemia associated with probable spontaneous transformation of lung adenocarcinoma to squamous cell carcinoma. This 81-year-old male with history of resected lung adenocarcinoma developed hypercalcemia. The peak albumin-corrected calcium was 13.4 mg/dL (normal 8.6–10.4) with ionized calcium 1.70 mmol/L (normal 1.09–1.29). Laboratory tests showed PTH 7 pg/ml (normal 11–51), PTHrP 43.7 pmol/L (normal

This document is a special issue of the International Journal of Molecular Sciences titled "Peptides for Health Benefits 2021." It discusses the prevalence of non-communicable diseases (NCDs) and their impact on global health. The document highlights the role of peptides in addressing various health conditions, including inflammation-related diseases, cancer, cardiovascular diseases, neurodegenerative diseases, and gastrointestinal disorders. It also explores the potential therapeutic applications of peptides in these areas, such as their anti-inflammatory, anticancer, cholesterol-lowering, neuroprotective, and cytoprotective effects. Additionally, the document discusses the use of peptides in tissue engineering for cell adhesion. Overall, this special issue provides valuable insights into the potential health benefits of peptides and their applications in various fields of medicine. [Extracted from the article]

The given text provides summaries of various studies and evaluations related to laboratory testing and diagnostics. These include studies on PFAS contamination, genotypic diagnosis of porphyria, interventions to improve laboratory testing appropriateness, an AI-driven support tool for urine culture test prediction, performance evaluation of rapid tests for C-reactive protein, and analytical performances of the ARK Pregabalin II Assay. The text also discusses the replacement of ISO 22870 with ISO 15189:2022 as the standard for point-of-care testing (POCT) and the challenges associated with operator training and certification. Additionally, the text includes studies on HbA1c measurement, disinfection protocols, Legionella pneumophila endocarditis diagnosis, and APTT reagent performance evaluation. These studies provide valuable insights into laboratory testing and diagnostics, emphasizing the importance of accreditation, performance assessment, accurate diagnosis, and establishing reliable thresholds for screening tests. [Extracted from the article]

Osteoporosis in men is an underappreciated public health issue, accounting for approximately 30% of the societal burden of osteoporosis. Although the prevalence of osteoporosis in men is lower, fracture-related morbidity and mortality rates exceed those of women. Abaloparatide is a synthetic, 34-amino acid peptide with homology to human parathyroid hormone-related protein (PTHrP), which favors bone formation by selective activation of PTH receptor type 1. In the Abaloparatide for the Treatment of Men With Osteoporosis (ATOM; NCT03512262) trial, 228 men with primary or hypogonadism-associated osteoporosis were randomized to receive subcutaneous injections of abaloparatide 80 μg or placebo. Abaloparatide significantly improved LS, TH, and FN BMD when compared with placebo. In this prespecified analysis, the proportion of men with a percent change from baseline of >0%, >3%, and > 6% in BMD at the LS, TH, and FN at 3, 6, and 12 mo and/or a shift in T-score category (based on LS and TH T-scores) at 12 mo was compared between the abaloparatide and placebo groups in ATOM. There were significantly more men with a BMD gain of >3% at all 3 anatomical sites in the abaloparatide than placebo group at month 6 (18/122 [14.8%] vs 1/70 [1.4%], P  = .002) and at month 12 (38/119 [31.9%] vs 1/66 [1.5%], P  < .0001). At month 3, more men treated with abaloparatide than placebo had a > 3% BMD increase at the LS (82/134 [61.2%] vs 21/68 [30.9%], P  < .0001). A greater proportion of men treated with abaloparatide had an improvement in T-score category from osteoporosis to low BMD or normal when compared with placebo. In conclusion, use of abaloparatide compared with placebo for 12 mo resulted in significant and rapid improvements in BMD in men with osteoporosis from the ATOM study. [ABSTRACT FROM AUTHOR]

Osteocytes respond to mechanical forces by controlling the function of osteoblasts and osteoclasts. Mechanical stimulation decreases osteocyte apoptosis and promotes bone formation. However, the lack of mechanical load induces osteocytes to favor osteoclastic migration and differentiation, ultimately resulting in bone mass loss. The primary cilium has been described as an important mechanoreceptor in bone cells. PTH1R, the type 1 receptor of parathyroid hormone (PTH), modulates the effects on osteoblasts, osteoclasts, and osteocytes upon activation by PTH or parathyroid hormone-related protein (PTHrP) in osteoblastic cells. Recently, it has been described that mechanical stimulation in osteocytes inhibits osteoclast recruitment and differentiation through a mechanism dependent on PTH1R and the primary cilium. Mechanical stimulation in osteocytes induces the translocation of PTH1R to the primary cilium in MLO-Y4 osteocytes. In this work, we propose to study whether PTHrP reproduces the effects observed with mechanical stimulation regarding the relocation of the receptor to the primary cilium and whether it is also capable of inhibiting osteoclast differentiation through the regulation of cytokines CXCL5 and IL-6. Our results show that stimulation with PTHrP (1-37) triggers a significant mobilization of PTH1R along with the primary cilium in MLO-Y4 osteocytic cells. Additionally, it is observed that PTHrP inhibits osteoclast differentiation through cytokines CXCL5 and IL-6. [ABSTRACT FROM AUTHOR]

Insulinoma INS‐1 cells are pancreatic beta cell tumors. Dinutuximab beta (DB) is a monoclonal antibody used in the treatment of neuroblastoma. The aim of this study is to investigate the effects of DB on pancreatic beta cell tumors at the molecular level. DB (Qarziba®) was available from EUSA Pharma. Streptozotocin (STZ) was used induce to cell cytotoxicity. DB was applied to the cells before or after the STZ application. KCND3, KCNN4, KCNK1, and PTHrP gene expression levels were analyzed by q‐RT‐PCR, and protein levels were analyzed by Western blotting. Analysis of glucose‐stimulated insulin secretion was performed. Ca+2 and CA19‐9 levels were determined by the ELISA kit. PERK, CHOP, HSP90, p‐c‐Jun, p‐Atf2, and p‐Elk1 protein levels were analyzed by simple WES. Decreased KCND3, KCNK1, and PTHrP protein levels and increased KCND3, KCNN4, KCNK1, and PTHrP gene expression levels were observed with DB applied after STZ application. Cell dysfunction was detected with DB applied before and after STZ application. Ca19‐9 and Ca+2 levels were increased with DB applied after STZ application. PERK, CHOP, and p‐Elk1 levels decreased, while HSP90 levels increased with DB applied after STZ application. CHOP, p‐Akt‐2, and p‐c‐Jun levels increased in the DB group. As a result, INS‐1 cells go to cell death via the ERK signaling pathway without ER stress and release insulin with the decrease of K+ channels and an increase in Ca+2 levels with DB applied after STZ application. Moreover, the cells proliferate via JNK signaling with DB application. DB holds promise for the treatment of insulinoma. The study should be supported by in vivo studies. [ABSTRACT FROM AUTHOR]

The mandibular condylar cartilage (MCC) is an essential component of the temporomandibular joint, which orchestrates the vertical growth of the mandibular ramus through endochondral ossification with distinctive modes of cell differentiation. Parathyroid hormone–related protein (PTHrP) is a master regulator of chondrogenesis; in the long bone epiphyseal growth plate, PTHrP expressed by resting zone chondrocytes promotes chondrocyte proliferation in the adjacent layer. However, how PTHrP regulates chondrogenesis in the MCC remains largely unclear. In this study, we used a Pthrp-mCherry knock-in reporter strain to map the localization of PTHrP+ cells in the MCC and define the function of PTHrP in the growing mandibular condyle. In the postnatal MCC of Pthrp mCherry/+ mice, PTHrP-mCherry was specifically expressed by cells in the superficial layer immediately adjacent to RUNX2-expressing cells in the polymorphic layer. PTHrP ligands diffused across the polymorphic and chondrocyte layers where its cognate receptor PTH1R was abundantly expressed. We further analyzed the mandibular condyle of Pthrp mCherry/mCherry mice lacking functional PTHrP protein (PTHrP-KO). At embryonic day (E) 18.5, the condylar process and MCC were significantly truncated in the PTHrP-KO mandible, which was associated with a significant reduction in cell proliferation across the polymorphic layer and a loss of SOX9+ cells in the chondrocyte layers. The PTHrP-KO MCC showed a transient increase in the number of Col10a1+ hypertrophic chondrocytes at E15.5, followed by a significant loss of these cells at E18.5, indicating that superficial layer–derived PTHrP prevents premature chondrocyte exhaustion in the MCC. The expression of Runx2, but not Sp7, was significantly reduced in the polymorphic layer of the PTHrP-KO MCC. Therefore, PTHrP released from cells in the superficial layer directly acts on cells in the polymorphic layer to promote proliferation of chondrocyte precursor cells and prevent their premature differentiation by maintaining Runx2 expression, revealing a unique PTHrP gradient-directed mechanism that regulates MCC chondrogenesis. [ABSTRACT FROM AUTHOR]

Bone is continuously in a state of building and renewal, though the process of remodeling that takes place at many sites asynchronously throughout the skeleton, with bone formation and resorption equal at these sites (bone multicellular units). Remodeling takes place on bone surfaces, both on trabeculae and in the cortex, and serves the purposes of replacing old bone or that damaged by microfractures throughout the skeleton. The bone loss and consequent osteoporotic fractures that result from excess resorption over formation have mainly been prevented or treated by antiresorptive drugs that inhibit osteoclast formation and/or activity. Virtually all of the evidence leading to acceptance of antiresorptive drugs as treatment has depended upon their prevention of vertebral fractures. In recent decades, new prospects came of anabolic treatments that partly restore bone volume and microstructure restore bone that has been lost. The first of these was parathyroid hormone (PTH), shown by daily injection to increase markers of bone formation and prevent fractures. This field of interest enlarged with the discovery of PTH-related protein (PTHrP), so closely related in structure and action to PTH. The structural relationship between PTH and PTHrP is important in assessing their physiological and pharmacological roles, with the N-terminal domains of the 2 having virtually equal actions on target cells. Abaloparatide, a peptide analogue based on the structures of PTHrP and PTH, has been approved in some countries as a therapy for osteoporosis. Treatment through the PTH receptor activation pathway, and probably with any anabolic therapy, needs to be followed by antiresorptive treatment in order to maintain bone that has been restored. No matter how effective anabolic therapies for the skeleton become, it seems highly likely that there will be a continuing need for antiresorptive drugs. [ABSTRACT FROM AUTHOR]

We report a rare case of adenosquamous carcinoma of the gallbladder which simultaneously produces granulocyte-colony-stimulating factor (G-CSF) and parathyroid hormone-related protein (PTHrP), confirmed serologically and histologically. A 71-year-old man was examined for a gallbladder tumor with multiple lymph nodes and liver metastases. Histopathological evaluation by endoscopic ultrasound fine-needle aspiration revealed adenosquamous carcinoma of the gallbladder. Laboratory data showed markedly elevated white blood cell (WBC) count of 34,700 µL and corrected serum calcium level of 14.9 mg/dL. Serum G-CSF (191 pg/mL) and PTHrP (23.1 pmol/L) levels were high. Zoledronic acid and calcitonin were administered to treat hypercalcemia, which normalized serum calcium levels. Gemcitabine–cisplatin chemotherapy was started for cStage IVB gallbladder cancer. After chemotherapy initiation, WBCs showed a rapid downward trend; however, the patient suddenly developed acute respiratory distress syndrome; thus, chemotherapy was discontinued. Subsequently, WBC count increased again, and the patient's overall condition deteriorated. The patient died on day 27. Immunohistochemistry using autopsy specimens demonstrated patchy staining for G-CSF in the squamous cell carcinoma portion and diffuse and weak positive staining for PTHrP in the squamous cell carcinoma and poorly differentiated adenocarcinoma portions of the tumor, suggesting simultaneous G-CSF and PTHrP production by the tumor. This is the first report of a patient with gallbladder cancer with serological and histological evidence for G-CSF and PTHrP production. [ABSTRACT FROM AUTHOR]

During lactation, changes in maternal calcium metabolism are necessary to provide adequate calcium for newborn skeletal development. The calcium in milk is derived from the maternal skeleton through a process thought to be mediated by the actions of parathyroid hormone-related protein (PTHrP) in combination with decreased circulating estrogen concentrations. After weaning, bone lost during lactation is rapidly regained. Most studies of bone metabolism in lactating women have been performed in Caucasian subjects. There are well-documented differences between African American (AA) and Caucasian (C) bone metabolism, including higher bone mineral density (BMD), lower risk of fracture, lower 25-hydroxyvitamin D (25(OH) D), and higher PTH in AA compared to C. In this prospective paired cohort study, BMD and markers of bone turnover were compared in self-identified AA and C mothers during lactation and after weaning. BMD decreased in both AA and C women during lactation, with similar decreases at the lumbar spine (LS) and greater bone loss in the C group at the femoral neck (FN) and total hip (TH), demonstrating that AA are not resistant to PTHrP during lactation. BMD recovery compared to the 2 week postpartum baseline was observed 6 months after weaning, though the C group did not have complete recovery at the FN. Increases in markers of bone formation and resorption during lactation were similar in AA and C. C-terminal telopeptide (CTX) decreased to 30% below post-pregnancy baseline in both groups 6 months after weaning, while procollagen type 1 N-terminal (P1NP) returned to baseline in the AA group and fell to below baseline in the C group. Further investigation is required to determine impacts on long term bone health for women who do not fully recover BMD before a subsequent pregnancy. [ABSTRACT FROM AUTHOR]

Prostate cancer is the only human malignancy that generates predominantly osteoblastic bone metastases, and osteoblastic bone metastases account for more than 90% of osseous metastases of prostate cancer. Prostate-specific antigen (PSA) plays an important role in the osteoblastic bone metastasis of prostate cancer, which can promote osteomimicry of prostate cancer cells, suppress osteoclast differentiation, and facilitate osteoblast proliferation and activation at metastatic sites. In the meantime, it can activate osteogenic factors, including insulin-like growth factor, transforming growth factor β2 and urokinase-type plasminogen activator, and meanwhile suppress osteolytic factors such as parathyroid hormone-related protein. To recapitulate, PSA plays a significant role in the osteoblastic predominance of prostate cancer bone metastasis and bone remodeling by regulating multiple cells and factors involved in osseous metastasis. [ABSTRACT FROM AUTHOR]

Background: Hypercalcemia of malignancy, as a paraneoplastic syndrome, is the most common metabolic disorder that accounts for 30% of malignancies and usually has a poor prognosis. Neuroendocrine tumors are uncommon and arise from neuroendocrine cells throughout the body. Actually, paraneoplastic hypercalcemia in neuroendocrine tumors is unusual and mostly associated with parathyroid hormone-related protein (PTHrP) secretion. Case presentation: We report a 51-year-old Iranian man who presented with nausea, vomiting, and significant weight loss for 1 month. Laboratory data revealed calcium of 26 mg/dl, accompanied by low level of PTH. Octreotide scan revealed a large donut-shaped octreotide avid lesion in the epigastric region at the right side of the mid-abdomen, with multiple varying size foci of abnormally increased radiotracer uptake in the epigastric region and both lobes of the liver. Endoscopic ultrasonography demonstrated a large heterogeneous mass lesion with irregular outline and good demarcation in the body of the pancreas with diffuse foci of calcification. Percutaneous biopsy of the liver mass demonstrated a well-differentiated neuroendocrine tumor (low grade) confirmed by immunohistochemistry with strongly positive chromogranin and synaptophysin stain. Hypercalcemia was treated with hydration, few sessions of hemodialysis, calcitonin, and denosumab injection. However, the patient developed symptomatic hypocalcemia. Oncology consultation led to prescription of long-acting octreotide 30 mg monthly and everolimus daily. Conclusion: Pancreatic neuroendocrine tumor could lead to malignant hypercalcemia; secretion of PTHrP is the most common cause, and signs and symptoms are usually milder than paraneoplastic syndrome due to hematologic and solid tumor. Generally, survival is better; however, its treatment is challenging, and primary debulking surgery is often required. A team approach to management is important at all points. [ABSTRACT FROM AUTHOR]

Key Clinical Message: A 76‐year‐old patient previously admitted to the cardiology department for replacement of a right ventricular lead on a double‐chamber pacemaker was admitted to the internal medicine department 15 days after for bronchopneumopathy. His past medical history was relevant for Type 2 diabetes mellitus, heart failure due to dilated hypokinetic heart disease, transcatheter aortic valve implantation (TAVI), and chronic myelomonocytic leukemia (CMML‐0) diagnosed in 2021. Twenty‐four hours after admission, the patient's general condition deteriorated abruptly, with the onset of drowsiness and psychomotor retardation. Laboratory exams revealed hypercalcemia at 4.18 mmol/L. Intensive hydration, calcitonin, and zoledronic acid were initiated and the patient was transferred to the nephrology intensive care unit where he underwent two sessions of hemodialysis to normalize serum calcium levels before readmission to internal medicine. Laboratory exams revealed low parathyroid hormone, normal 1‐25‐OH vitamin D, and increased parathyroid hormone‐related peptide. Thoracoabdominal and positron emission tomography (PET) scan showed diffuse abdominopelvic peritoneal carcinosis associated with low‐grade pleural effusion and multiple supra‐ and sub‐diaphragmatic adenopathies, leading to a search for a solid tumor. The patient's clinical condition worsened leading to a transfer to the intensive care unit. The biopsy of a peritoneal carcinosis nodule confirmed the diagnosis of diffuse large B‐cell lymphoma. Specific treatments were unsuccessful and the patient expired. [ABSTRACT FROM AUTHOR]

Parathyroid hormone type 1 receptor (PTH1R), a member of the G-protein-coupled receptor family, is extensively expressed in the human body and is involved in various processes such as embryonic development, calcium and phosphorus homeostasis, body metabolism and tumorigenesis. PTH1R is highly expressed in the kidney, and its activation is involved in the development and progression of renal diseases though multiple mechanisms and complicated pathways, and is closely associated with a variety of renal diseases such as diabetic nephropathy, glomerulonephritis, acute kidney injury, and chronic kidney disease. This article reviews recent studies about the function of PTH1R, and its role and mechanism of action in renal diseases, and provides an in-depth discussion on the relationship and related mechanisms between PTH1R and kidney diseases, offering new ideas for the diagnosis and treatment of kidney diseases.

A case study describes a 9-year-old Beagle dog with a 1-month history of cervical pain and progressive tetraparesis, initially responsive to nonsteroidal anti-inflammatory therapy, presenting with hypercalcemia, mild hyponatremia, mild hypomagnesemia and increased ALP. Imaging revealed a cranial mediastinal soft tissue mass with metastasis to the lung and liver, along with vertebral invasion, leading to euthanasia due to poor prognosis.

Key Clinical Message A 76‐year‐old patient previously admitted to the cardiology department for replacement of a right ventricular lead on a double‐chamber pacemaker was admitted to the internal medicine department 15 days after for bronchopneumopathy. His past medical history was relevant for Type 2 diabetes mellitus, heart failure due to dilated hypokinetic heart disease, transcatheter aortic valve implantation (TAVI), and chronic myelomonocytic leukemia (CMML‐0) diagnosed in 2021. Twenty‐four hours after admission, the patient's general condition deteriorated abruptly, with the onset of drowsiness and psychomotor retardation. Laboratory exams revealed hypercalcemia at 4.18 mmol/L. Intensive hydration, calcitonin, and zoledronic acid were initiated and the patient was transferred to the nephrology intensive care unit where he underwent two sessions of hemodialysis to normalize serum calcium levels before readmission to internal medicine. Laboratory exams revealed low parathyroid hormone, normal 1‐25‐OH vitamin D, and increased parathyroid hormone‐related peptide. Thoracoabdominal and positron emission tomography (PET) scan showed diffuse abdominopelvic peritoneal carcinosis associated with low‐grade pleural effusion and multiple supra‐ and sub‐diaphragmatic adenopathies, leading to a search for a solid tumor. The patient's clinical condition worsened leading to a transfer to the intensive care unit. The biopsy of a peritoneal carcinosis nodule confirmed the diagnosis of diffuse large B‐cell lymphoma. Specific treatments were unsuccessful and the patient expired.