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1.
J Histochem Cytochem ; 72(5): 309-327, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38725403

RESUMEN

To clarify the cellular mechanism of cortical porosity induced by intermittent parathyroid hormone (PTH) administration, we examined the femoral cortical bone of mice that received 40 µg/kg/day (four times a day) human PTH (hPTH) (1-34). The PTH-driven cortical porosity initiated from the metaphyseal region and chronologically expanded toward the diaphysis. Alkaline phosphatase (ALP)-positive osteoblasts in the control mice covered the cortical surface, and endomucin-positive blood vessels were distant from these osteoblasts. In PTH-administered mice, endomucin-reactive blood vessels with TRAP-positive penetrated the ALP-positive osteoblast layer, invading the cortical bone. Statistically, the distance between endomucin-positive blood vessels and the cortical bone surface abated after PTH administration. Transmission electron microscopic observation demonstrated that vascular endothelial cells often pass through the flattened osteoblast layer and accompanied osteoclasts in the deep region of the cortical bone. The cell layers covering mature osteoblasts thickened with PTH administration and exhibited ALP, α-smooth muscle actin (αSMA), vascular cell adhesion molecule-1 (VCAM1), and receptor activator of NF-κB ligand (RANKL). Within these cell layers, osteoclasts were found near endomucin-reactive blood vessels. In PTH-administered femora, osteocytes secreted Dkk1, a Wnt inhibitor that affects angiogenesis, and blood vessels exhibited plasmalemma vesicle-associated protein, an angiogenic molecule. In summary, endomucin-positive blood vessels, when accompanied by osteoclasts in the ALP/αSMA/VCAM1/RANKL-reactive osteoblastic cell layers, invade the cortical bone, potentially due to the action of osteocyte-derived molecules such as DKK1.


Asunto(s)
Hueso Cortical , Células Endoteliales , Hormona Paratiroidea , Animales , Ratones , Hormona Paratiroidea/farmacología , Hormona Paratiroidea/administración & dosificación , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Hueso Cortical/efectos de los fármacos , Hueso Cortical/metabolismo , Porosidad , Masculino , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Inmunohistoquímica , Fémur/efectos de los fármacos , Fémur/irrigación sanguínea , Fémur/metabolismo , Humanos
2.
Biochem Biophys Res Commun ; 711: 149888, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38603833

RESUMEN

OBJECTIVE: To investigate the effect of intermittent parathyroid hormone (iPTH) administration on pathological new bone formation during treatment of ankylosing spondylitis-related osteoporosis. METHODS: Animal models with pathological bone formation caused by hypothetical AS pathogenesis received treatment with iPTH. We determined the effects of iPTH on bone loss and the formation of pathological new bone with micro-computed tomography (micro-CT) and histological examination. In addition, the tamoxifen-inducible conditional knockout mice (CAGGCre-ERTM; PTHflox/flox, PTH-/-) was established to delete PTH and investigate the effect of endogenous PTH on pathological new bone formation. RESULTS: iPTH treatment significantly improved trabecular bone mass in the modified collagen-induced arthritis (m-CIA) model and unbalanced mechanical loading models. Meanwhile, iPTH treatment did not enhance pathological new bone formation in all types of animal models. Endogenous PTH deficiency had no effects on pathological new bone formation in unbalanced mechanical loading models. CONCLUSION: Experimental animal models of AS treated with iPTH show improvement in trabecular bone density, but not entheseal pathological bone formation,indicating it may be a potential treatment for inflammatory bone loss does in AS.


Asunto(s)
Osteogénesis , Hormona Paratiroidea , Animales , Hormona Paratiroidea/administración & dosificación , Hormona Paratiroidea/farmacología , Hormona Paratiroidea/uso terapéutico , Osteogénesis/efectos de los fármacos , Ratones , Osteoporosis/tratamiento farmacológico , Osteoporosis/patología , Ratones Noqueados , Masculino , Microtomografía por Rayos X , Espondilitis Anquilosante/tratamiento farmacológico , Espondilitis Anquilosante/patología , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Densidad Ósea/efectos de los fármacos
3.
J Orthop Surg Res ; 17(1): 130, 2022 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-35241115

RESUMEN

BACKGROUND: To date, the usefulness of parathyroid hormone [PTH (1-34)] in distraction osteogenesis has been reported in several studies. We aimed to determine the optimal timing of PTH (1-34) administration in a rabbit distraction osteogenesis model. METHODS: The lower hind leg of a Japanese white rabbit was externally fixed, and tibial osteotomy was performed. One week after the osteotomy, bone lengthening was carried out at 0.375 mm/12 h for 2 weeks. After 5 weeks, the lower leg bone was collected. Bone mineral density (BMD), peripheral quantitative computed tomography (pQCT), micro-computed tomography (micro-CT), and mechanical tests were performed on the distracted callus. The rabbits were divided into three groups according to the timing of PTH (1-34) administration: 4 weeks during the distraction and consolidation phases (group D + C), 2 weeks of the distraction phase (group D), and the first 2 weeks of the consolidation phase (group C). A control group (group N) was administered saline for 4 weeks during the distraction and consolidation phases. Furthermore, to obtain histological findings, lower leg bones were collected from each rabbit at 2, 3, and 4 weeks after osteotomy, and tissue sections of the distracted callus were examined histologically. RESULTS: The BMD was highest in group C and was significantly higher than group D. In pQCT, the total cross-sectional area was significantly higher in groups D + C, D, and C than group N, and the cortical bone area was highest in group C and was significantly higher than group D. In micro-CT, group C had the highest bone mass and number of trabeculae. Regarding the mechanical test, group C had the highest callus failure strength, and this value was significantly higher compared to group N. There was no significant difference between groups D and N. The histological findings revealed that the distracted callus mainly consisted of endochondral ossification in the distraction phase. In the consolidation phase, the chondrocytes were almost absent, and intramembranous ossification was the main type of ossification. CONCLUSION: We found that the optimal timing of PTH (1-34) administration is during the consolidation phase, which is mainly characterized by intramembranous ossification.


Asunto(s)
Callo Óseo/efectos de los fármacos , Osteogénesis por Distracción/métodos , Osteogénesis/efectos de los fármacos , Hormona Paratiroidea/administración & dosificación , Animales , Densidad Ósea , Callo Óseo/diagnóstico por imagen , Hormona Paratiroidea/farmacología , Conejos , Microtomografía por Rayos X
4.
Int J Mol Sci ; 23(2)2022 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-35055125

RESUMEN

PTH induces phosphorylation of the transcriptional coregulator NACA on serine 99 through Gαs and PKA. This leads to nuclear translocation of NACA and expression of the target gene Lrp6, encoding a coreceptor of the PTH receptor (PTH1R) necessary for full anabolic response to intermittent PTH (iPTH) treatment. We hypothesized that maintaining enough functional PTH1R/LRP6 coreceptor complexes at the plasma membrane through NACA-dependent Lrp6 transcription is important to ensure maximal response to iPTH. To test this model, we generated compound heterozygous mice in which one allele each of Naca and Lrp6 is inactivated in osteoblasts and osteocytes, using a knock-in strain with a Naca99 Ser-to-Ala mutation and an Lrp6 floxed strain (test genotype: Naca99S/A; Lrp6+/fl;OCN-Cre). Four-month-old females were injected with vehicle or 100 µg/kg PTH(1-34) once daily, 5 days a week for 4 weeks. Control mice showed significant increases in vertebral trabecular bone mass and biomechanical properties that were abolished in compound heterozygotes. Lrp6 expression was reduced in compound heterozygotes vs. controls. The iPTH treatment increased Alpl and Col1a1 mRNA levels in the control but not in the test group. These results confirm that NACA and LRP6 form part of a common genetic pathway that is necessary for the full anabolic effect of iPTH.


Asunto(s)
Anabolizantes/administración & dosificación , Células Madre Embrionarias/citología , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/genética , Chaperonas Moleculares/genética , Hormona Paratiroidea/administración & dosificación , Anabolizantes/farmacología , Animales , Línea Celular , Membrana Celular/metabolismo , Células Madre Embrionarias/efectos de los fármacos , Células Madre Embrionarias/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Sustitución del Gen , Ratones , Chaperonas Moleculares/metabolismo , Mutagénesis Sitio-Dirigida , Osteoblastos/metabolismo , Osteocitos/metabolismo , Hormona Paratiroidea/farmacología , Fosforilación , Transducción de Señal/efectos de los fármacos , Microtomografía por Rayos X
5.
J Clin Endocrinol Metab ; 107(1): e372-e385, 2022 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-34347093

RESUMEN

CONTEXT: Hypoparathyroidism is characterized by insufficient levels of parathyroid hormone (PTH). TransCon PTH is an investigational long-acting prodrug of PTH(1-34) for the treatment of hypoparathyroidism. OBJECTIVE: This work aimed to investigate the safety, tolerability, and efficacy of daily TransCon PTH in adults with hypoparathyroidism. METHODS: This phase 2, randomized, double-blind, placebo-controlled 4-week trial with open-label extension enrolled 59 individuals with hypoparathyroidism. Interventions included TransCon PTH 15, 18, or 21 µg PTH(1-34)/day or placebo for 4 weeks, followed by a 22-week extension during which TransCon PTH dose was titrated (6-60 µg PTH[1-34]/day). RESULTS: By Week 26, 91% of participants treated with TransCon PTH achieved independence from standard of care (SoC, defined as active vitamin D = 0 µg/day and calcium [Ca] ≤ 500 mg/day). Mean 24-hour urine Ca (uCa) decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while normal serum Ca (sCa) was maintained and serum phosphate and serum calcium-phosphate product fell within the normal range. By Week 26, mean scores on the generic 36-Item Short Form Health Survey domains increased from below normal at baseline to within the normal range. The Hypoparathyroidism Patient Experience Scale symptom and impact scores improved through 26 weeks. TransCon PTH was well tolerated with no treatment-related serious or severe adverse events. CONCLUSION: TransCon PTH enabled independence from oral active vitamin D and reduced Ca supplements (≤ 500 mg/day) for most participants, achieving normal sCa, serum phosphate, uCa, serum calcium-phosphate product, and demonstrating improved health-related quality of life. These results support TransCon PTH as a potential hormone replacement therapy for adults with hypoparathyroidism.


Asunto(s)
Terapia de Reemplazo de Hormonas/métodos , Hipoparatiroidismo/tratamiento farmacológico , Hormona Paratiroidea/administración & dosificación , Adulto , Anciano , Calcio/administración & dosificación , Calcio/sangre , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/efectos adversos , Método Doble Ciego , Esquema de Medicación , Femenino , Terapia de Reemplazo de Hormonas/efectos adversos , Humanos , Hipoparatiroidismo/sangre , Hipoparatiroidismo/complicaciones , Hipoparatiroidismo/diagnóstico , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/efectos adversos , Hormona Paratiroidea/sangre , Medición de Resultados Informados por el Paciente , Placebos/administración & dosificación , Placebos/efectos adversos , Profármacos/administración & dosificación , Profármacos/efectos adversos , Calidad de Vida , Resultado del Tratamiento , Vitamina D/administración & dosificación , Vitamina D/sangre
6.
Biomed Pharmacother ; 145: 112390, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34839260

RESUMEN

Osteoporosis leads to excessive bone resorption which is not accompanied by equal amount of bone formation. PTH (1-34) forms the mainstay of bone anabolic therapy. Intermittent PTH (iPTH) has the ability to reconstruct skeleton, a property not shared by other anti-resorptives. In initial phases of PTH treatment, bone formation exceeds bone resorption. However, gradually this phase is replaced by increased bone resorption. Thus, a replacement post PTH discontinuation is much needed. Studies with bisphosphonates and Denosumab post PTH withdrawal have yielded promising but variable results. Thus, there is scope for trying new combinations. Our previous studies have shown the superior skeletal effects of neutralizing IL17 antibody (NIL17) over anti-RANKL antibody. Thus, here we investigated if sequential treatment of NIL17 after PTH withdrawal (SHIFT) could serve as a promising therapeutic approach for osteoporosis treatment. Our results show that PTH withdrawal (PTH-W) led to mitigation of its anabolic effects as evidenced by reduced BMD, bone trabecular and cortical microarchitectural parameters. In the continuous PTH (PTH-C) and the Shift group, all these parameters were preserved as par with the sham group. Shift therapy also significantly increased PINP levels. Most importantly, serum CTX-I levels and osteoclast numbers, which were elevated in PTH groups were significantly suppressed in NIL17 monotherapy and shift group. Also, expression of FOXO1 and ATF-4, the main regulators of redox balance and function in osteoblasts, were found to be enhanced maximally in the sequential therapy group. Our study thus advocates use of NIL17 as a replacement therapeutic option post PTH discontinuation.


Asunto(s)
Anticuerpos Neutralizantes/farmacología , Interleucina-17/inmunología , Osteoporosis/prevención & control , Hormona Paratiroidea/farmacología , Factor de Transcripción Activador 4/genética , Animales , Anticuerpos Neutralizantes/administración & dosificación , Resorción Ósea/prevención & control , Huesos/metabolismo , Femenino , Proteína Forkhead Box O1/genética , Ratones , Ratones Endogámicos BALB C , Osteoblastos/metabolismo , Oxidación-Reducción , Estrés Oxidativo/fisiología , Hormona Paratiroidea/administración & dosificación
7.
Mol Pharm ; 18(9): 3260-3271, 2021 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-34482698

RESUMEN

Hypoparathyroidism (HP) is a rare disease with clinical manifestations of hypocalcemia and hyperphosphatemia, resulting from deficient or absent parathyroid hormone (PTH) secretion. Conventional treatment for patients with HP involves extensive calcium and vitamin D supplementation. In 2015, PTH1-84 was approved by the United States Food and Drug Administration as an adjunct for HP patients who cannot be well-controlled on conventional treatment. However, PTH1-84 therapy requires a daily injection, leading to poor patient compliance. The purpose of this study was to develop a long-acting PTH1-34 analogue by increasing its affinity to albumin. Three PTH1-34 variants were generated by substituting two of the three lysine (Lys) residues with arginine, reserving a single Lys as the modification site in each sequence. A series of side chains, containing fatty acid, deoxycholic acid, or biotin groups, were synthesized to modify these PTH1-34 variants by using a solid-liquid phase synthesis approach. In vitro bioactivity and albumin affinity tests were used to screen these new PTH1-34 analogues. Finally, Lys27-AAPC was selected from 69 synthesized analogues as a candidate therapeutic compound because it retained potency and exhibited a high albumin-binding capacity. In pharmacodynamic experiments, Lys27-AAPC demonstrated enhanced and prolonged efficacy in serum calcium elevating relative to PTH1-84. Moreover, a lyophilized powder for injection containing Lys27-AAPC was developed for further testing and represented a potential long-acting HP treatment.


Asunto(s)
Hipoparatiroidismo/tratamiento farmacológico , Hormona Paratiroidea/administración & dosificación , Péptidos/administración & dosificación , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Calcio/sangre , Esquema de Medicación , Semivida , Humanos , Hipoparatiroidismo/sangre , Inyecciones Subcutáneas , Masculino , Cumplimiento de la Medicación , Ratones , Modelos Animales , Hormona Paratiroidea/genética , Hormona Paratiroidea/farmacocinética , Péptidos/genética , Péptidos/farmacocinética , Ratas , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacocinética , Relación Estructura-Actividad
8.
Cells ; 10(8)2021 08 11.
Artículo en Inglés | MEDLINE | ID: mdl-34440827

RESUMEN

Non-unions continue to present a challenge to trauma surgeons, as current treatment options are limited, duration of treatment is long, and the outcome often unsatisfactory. Additionally, standard treatment with autologous bone grafts is associated with comorbidity at the donor site. Therefore, alternatives to autologous bone grafts and further therapeutic strategies to improve on the outcome and reduce cost for care providers are desirable. In this study in Sprague-Dawley rats we employed a recently established sequential defect model, which provides a platform to test new potential therapeutic strategies on non-unions while gaining mechanistic insight into their actions. The effects of a combinatorial treatment of a bone graft substitute (HACaS+G) implantation and systemic PTH administration was assessed by µ-CT, histological analysis, and bio-mechanical testing and compared to monotreatment and controls. Although neither PTH alone nor the combination of a bone graft substitute and PTH led to the formation of a stable union, our data demonstrate a clear osteoinductive and osteoconductive effect of the bone graft substitute. Additionally, PTH administration was shown to induce vascularization, both as a single adjuvant treatment and in combination with the bone graft substitute. Thus, systemic PTH administration is a potential synergistic co-treatment to bone graft substitutes.


Asunto(s)
Sustitutos de Huesos/administración & dosificación , Fracturas no Consolidadas/terapia , Neovascularización Fisiológica/efectos de los fármacos , Hormona Paratiroidea/administración & dosificación , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Regeneración Ósea/efectos de los fármacos , Remodelación Ósea/efectos de los fármacos , Sustitutos de Huesos/farmacología , Trasplante Óseo , Sulfato de Calcio/administración & dosificación , Sulfato de Calcio/farmacología , Terapia Combinada , Combinación de Medicamentos , Durapatita/administración & dosificación , Durapatita/farmacología , Fracturas del Fémur/terapia , Gentamicinas/administración & dosificación , Gentamicinas/farmacología , Receptores de Lipopolisacáridos/metabolismo , Ratas , Ratas Sprague-Dawley
10.
Nat Commun ; 12(1): 2136, 2021 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-33837198

RESUMEN

Osteoclastic bone resorption and osteoblastic bone formation/replenishment are closely coupled in bone metabolism. Anabolic parathyroid hormone (PTH), which is commonly used for treating osteoporosis, shifts the balance from osteoclastic to osteoblastic, although it is unclear how these cells are coordinately regulated by PTH. Here, we identify a serine protease inhibitor, secretory leukocyte protease inhibitor (SLPI), as a critical mediator that is involved in the PTH-mediated shift to the osteoblastic phase. Slpi is highly upregulated in osteoblasts by PTH, while genetic ablation of Slpi severely impairs PTH-induced bone formation. Slpi induction in osteoblasts enhances its differentiation, and increases osteoblast-osteoclast contact, thereby suppressing osteoclastic function. Intravital bone imaging reveals that the PTH-mediated association between osteoblasts and osteoclasts is disrupted in the absence of SLPI. Collectively, these results demonstrate that SLPI regulates the communication between osteoblasts and osteoclasts to promote PTH-induced bone anabolism.


Asunto(s)
Resorción Ósea/tratamiento farmacológico , Osteogénesis/fisiología , Hormona Paratiroidea/administración & dosificación , Inhibidor Secretorio de Peptidasas Leucocitarias/metabolismo , Animales , Resorción Ósea/patología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Línea Celular , Modelos Animales de Enfermedad , Femenino , Fémur/citología , Fémur/diagnóstico por imagen , Fémur/efectos de los fármacos , Fémur/patología , Humanos , Masculino , Ratones , Ratones Noqueados , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Osteogénesis/efectos de los fármacos , Cultivo Primario de Células , RNA-Seq , Inhibidor Secretorio de Peptidasas Leucocitarias/genética , Regulación hacia Arriba/efectos de los fármacos , Microtomografía por Rayos X
11.
Drug Deliv ; 28(1): 487-498, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33657948

RESUMEN

For efficient intranasal transport of parathyroid hormone (1-34) [PTH(1-34)], there is a great medical need to investigate permeation enhancers for intranasal formulations. In this study, the development of PTH(1-34) intranasal formulations was conducted. Based on conformation and chemical stability studies, the most preferable aqueous environment was determined to be 0.008 M acetate buffer solution (ABS). Subsequently, citric acid and Kolliphor® HS·15 were compared as permeation enhancers. The mechanisms of action of citric acid and Kolliphor® HS·15 were investigated using an in vitro model of nasal mucosa, and Kolliphor® HS·15 led to higher permeability of fluorescein isothiocyanate-labeled PTH(1-34) (FITC-PTH) by enhancing both the transcellular and paracellular routes. Moreover, citric acid showed severe mucosal toxicity resulting in cilia shedding, while Kolliphor® HS·15 did not cause obvious mucosa damage. Finally, Kolliphor® HS·15 was studied as a permeation enhancer using a liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The results showed that 5% and 10% Kolliphor® HS·15 increased the bioavailability of PTH(1-34) to 14.76% and 30.87%, respectively. In conclusion, an effective and biosafe PTH(1-34) intranasal formulation was developed by using 10% Kolliphor® HS·15 as a permeation enhancer. Intranasal formulations with higher concentrations of Kolliphor® HS·15 for higher bioavailability of PTH(1-34) could be further researched.


Asunto(s)
Excipientes/química , Mucosa Nasal/metabolismo , Hormona Paratiroidea/administración & dosificación , Administración Intranasal , Animales , Anuros , Disponibilidad Biológica , Cromatografía Liquida , Ácido Cítrico/química , Ácido Cítrico/toxicidad , Excipientes/toxicidad , Femenino , Masculino , Hormona Paratiroidea/farmacocinética , Hormona Paratiroidea/toxicidad , Permeabilidad , Polietilenglicoles/química , Polietilenglicoles/toxicidad , Ratas , Ratas Sprague-Dawley , Estearatos/química , Estearatos/toxicidad , Espectrometría de Masas en Tándem
12.
Elife ; 102021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33646122

RESUMEN

Osteoarthritis, a highly prevalent degenerative joint disorder, is characterized by joint pain and disability. Available treatments fail to modify osteoarthritis progression and decrease joint pain effectively. Here, we show that intermittent parathyroid hormone (iPTH) attenuates osteoarthritis pain by inhibiting subchondral sensory innervation, subchondral bone deterioration, and articular cartilage degeneration in a destabilized medial meniscus (DMM) mouse model. We found that subchondral sensory innervation for osteoarthritis pain was significantly decreased in PTH-treated DMM mice compared with vehicle-treated DMM mice. In parallel, deterioration of subchondral bone microarchitecture in DMM mice was attenuated by iPTH treatment. Increased level of prostaglandin E2 in subchondral bone of DMM mice was reduced by iPTH treatment. Furthermore, uncoupled subchondral bone remodeling caused by increased transforming growth factor ß signaling was regulated by PTH-induced endocytosis of the PTH type 1 receptor-transforming growth factor ß type 2 receptor complex. Notably, iPTH improved subchondral bone microarchitecture and decreased level of prostaglandin E2 and sensory innervation of subchondral bone in DMM mice by acting specifically through PTH type 1 receptor in Nestin+ mesenchymal stromal cells. Thus, iPTH could be a potential disease-modifying therapy for osteoarthritis.


Over time the cartilage between our bones gets worn down, and this can lead to a painful joint disorder known as osteoarthritis. Nearly 40 million people with osteoarthritis in the United States experience chronic pain. Although there are a number of drugs available for these patients, none of them provide sustained pain relief, and some have substantial side effects when ingested over a long period of time. Bone tissue is continuously broken down into minerals, such as calcium, that can be reabsorbed into the blood. In 2013, a group of researchers found that the tissue in the layer of bone below the cartilage ­ known as the subchondral bone ­ is reabsorbed and replaced incorrectly in patients with osteoarthritis. This irregular 'remodeling' stimulates nerve cells to grow into the subchondral layer, leading to increased sensitivity in the joint. A protein called parathyroid hormone, or PTH for short, plays an important role in the loss and formation of bone. A drug containing PTH is used to treat patients with another bone condition called osteoporosis, and could potentially work as a treatment for osteoarthritis pain. To investigate this, Sun et al. ­ including some of the researchers involved in the 2013 study ­ tested this drug on a mouse model that mimics the symptoms of osteoarthritis. This revealed that PTH significantly decreases the number of nerves present in the subchondral bone, which caused the mice to experience less pain. PTH also slowed down the progression of osteoarthritis, by preventing the cartilage on the subchondral layer from deteriorating as quickly. Sun et al. found that the subchondral bones of treated mice also had a more stable structure and reduced levels of a protein involved in the reabsorption of bone. The results suggest that PTH is able to correct the errors in bone remodeling caused by osteoarthritis, and that this drug could potentially alleviate patients' chronic pain. This drug has already been approved by the US Food and Drug Administration (FDA), and could be used in clinical trials to see if PTH has the same beneficial effects on patients with osteoarthritis.


Asunto(s)
Remodelación Ósea/efectos de los fármacos , Osteoartritis/tratamiento farmacológico , Dolor/tratamiento farmacológico , Hormona Paratiroidea/farmacología , Animales , Huesos/inervación , Huesos/patología , Dinoprostona , Modelos Animales de Enfermedad , Miembro Posterior , Masculino , Menisco/lesiones , Ratones Endogámicos C57BL , Ratones Transgénicos , Hormona Paratiroidea/administración & dosificación
13.
Sci Rep ; 11(1): 54, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33420145

RESUMEN

The purpose of this study was to investigate the effect of administering intermittent parathyroid hormone (iPTH) before tooth extraction versus after tooth extraction on the risk of developing MRONJ in experimental animal model. Twenty-five ovariectomized rats received 6 weeks of bisphosphonate therapy. They were classified into 3 groups, based on the timing of the medication, as Control, Pre-PTH and Post-PTH groups. For Control group, normal saline was administered before and after tooth extraction. iPTH was administered during 4 weeks before tooth extraction for Pre-PTH group and after tooth extraction for Post-PTH group. The animals were euthanized 8 weeks after tooth extraction. Macroscopic, histological, micro-computed tomography (micro-CT), and histomorphometric examinations were conducted. The incidences of impaired healing were 11.11% both in Pre-PTH and Post-PTH groups, which was lower than the Control group (42.86%). Bone healing in the extraction socket, based on micro-CT and histomorphometry evaluations, was best in Post-PTH and worst in Control group. The Pre-PTH group showed moderate healing pattern. Despite of limitations in this study, the authors identified Pre-PTH group seems to have positive effect on extraction socket healing. With regard to timing, administering iPTH after tooth extraction was superior to applying it before tooth extraction.


Asunto(s)
Difosfonatos/uso terapéutico , Ovariectomía , Hormona Paratiroidea/uso terapéutico , Alveolo Dental/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Animales , Femenino , Ovariectomía/efectos adversos , Hormona Paratiroidea/administración & dosificación , Ratas , Ratas Sprague-Dawley , Extracción Dental/efectos adversos , Extracción Dental/métodos , Alveolo Dental/diagnóstico por imagen , Microtomografía por Rayos X
14.
Clin Endocrinol (Oxf) ; 94(3): 377-383, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32955743

RESUMEN

CONTEXT: The monogenic disorder autoimmune polyendocrine syndrome type 1 (APS-1) or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) manifests frequently with hypoparathyroidism, which requires treatment with oral supplementation with calcium and active vitamin D analogs. The majority of APS-1/APECED patients also suffer from intestinal malabsorption, which complicates the management of hypoparathyroidism and may lead to refractory severe hypocalcaemia. In such situations, reliance on intravenous calcium carries a high risk of nephrocalcinosis and renal damage. METHODS: Here, we report our experience of periprocedural subcutaneous administration of recombinant human parathyroid hormone (rhPTH 1-34) in APS-1/APECED patients. Serum calcium was measured up to five times within the 36-hour period starting the evening before the scheduled procedure and ending the morning following the procedure. RESULTS: Twenty-seven APS-1/APECED patients with hypoparathyroidism (aged 4-67 years) underwent 31 invasive gastrointestinal and/or pulmonary procedures. The patients received an average rhPTH1-34 dose of 9.6 ± 1.4 µg by subcutaneous injection. 92% of the adults and 54% of children in our cohort had evidence of nephrocalcinosis. Mean calcium levels remained stable and ranged from 2.06 to 2.17 mmol/L with minimal fluctuation. None of our patients experienced periprocedural adverse events connected with hypocalcaemia. CONCLUSION: rhPTH 1-34 is an alternative to conventional therapy in patients with APS-1/APECED and hypoparathyroidism undergoing invasive procedures. Subcutaneous PTH1-34 given directly before and after procedures resulted in well-controlled serum calcium levels maintained in the low-normal range and avoided the need for intravenous calcium which may contribute to renal calcifications and tubular damage.


Asunto(s)
Hipocalcemia , Hipoparatiroidismo , Hormona Paratiroidea , Poliendocrinopatías Autoinmunes , Adulto , Calcio/sangre , Niño , Humanos , Hipocalcemia/tratamiento farmacológico , Hipoparatiroidismo/tratamiento farmacológico , Hormona Paratiroidea/administración & dosificación , Poliendocrinopatías Autoinmunes/sangre , Poliendocrinopatías Autoinmunes/tratamiento farmacológico
15.
J Cell Physiol ; 236(3): 2070-2086, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32740946

RESUMEN

Intermittent parathyroid hormone (PTH) promotes periodontal repair, but the underlying mechanisms remained unclear. Recent studies found that ephrinB2-EPHB4 forward signaling mediated the anabolic effect of PTH in bone homeostasis. Considering the similarities between cementum and bone, we aimed to examine the therapeutic effect of PTH on resorbed roots and explore the role of forward signaling in this process. In vivo experiments showed that intermittent PTH significantly accelerated the regeneration of root resorption and promoted expression of EPHB4 and ephrinB2. When the signaling was blocked, the resorption repair was also delayed. In vitro studies showed that intermittent PTH promoted the expression of EPHB4 and ephrinB2 in OCCM-30 cells. The effects of PTH on the mineralization capacity of OCCM-30 cells was mediated through the ephrinB2-EPHB4 forward signaling. These results support the premise that the anabolic effects of intermittent PTH on the regeneration of root resorption is via the ephrinB2-EPHB4 forward signaling pathway.


Asunto(s)
Cementogénesis/efectos de los fármacos , Efrina-B2/metabolismo , Hormona Paratiroidea/farmacología , Receptor EphB4/metabolismo , Transducción de Señal , Animales , Línea Celular , Cemento Dental/efectos de los fármacos , Cemento Dental/metabolismo , Masculino , Ratones , Modelos Biológicos , Hormona Paratiroidea/administración & dosificación , Ratas Wistar , Regeneración/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Tomografía Computarizada por Rayos X , Raíz del Diente/diagnóstico por imagen , Raíz del Diente/efectos de los fármacos
16.
JAMA Otolaryngol Head Neck Surg ; 147(2): 135-143, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33211086

RESUMEN

Importance: Intraoperative parathyroid hormone (ioPTH) is a surgical adjunct that has been increasingly used during minimally invasive parathyroidectomy (MIP). Despite its growing popularity, to our knowledge a meta-analysis comparing MIP with ioPTH vs MIP without ioPTH has not yet been conducted. Objective: To evaluate the safety and efficacy of MIP with ioPTH for treatment of primary hyperparathyroidism. Data Sources: A systematic search of the databases PubMed, Embase, Scopus, Web of Science, and Cochrane Collaboration was performed to identify studies that compared MIP with and without ioPTH. Data were analyzed between August and September 2019. Study Selection: Inclusion criteria consisted of randomized clinical trials and observational studies with a retrospective/prospective design, comparing MIP using ioPTH vs MIP not using ioPTH for treatment of primary hyperparathyroidism. Eligible studies had to present odds ratio (OR), risk ratio, or hazard ratio estimates (with 95% CI), standard errors, or number of events necessary to calculate these for the outcome of interest rate. Studies involving patients with secondary or tertiary hyperparathyroidism or those with multiple endocrine neoplasia syndrome were excluded. Data Extraction: Two reviewers independently reviewed the literature according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Dichotomous variables were pooled as ORs while continuous variables were compared using weighted mean differences. Quality assessment was performed using the Newcastle-Ottawa Scale. Main Outcomes and Measures: The primary outcome was rate of cure. Secondary outcomes included need for reoperation, need for bilateral neck exploration, morbidity, and length of surgery. Results: A total of 12 studies, involving 2290 patients with primary hyperparathyroidism, were eligible for inclusion. The median (SD) age of participants was 60.1 (11.8) years and 77.3% of participants were women. The median Newcastle-Ottawa score was 7. Patients who underwent MIP with ioPTH had higher cure rates (OR, 3.88; 95% CI, 2.12-7.10; P < .001). There was a greater need for reoperation in the group of patients who had surgery without ioPTH (OR, 0.40; 95% CI, 0.19-0.86; P = .02). There was a trend toward longer operating times/increased duration of surgery in the ioPTH group; however, this did not reach statistical significance (weighted mean difference, 21.62 minutes; 95% CI, -0.93 to 44.17 minutes; P = .06). The use of ioPTH was associated with higher rates of bilateral neck exploration (OR, 3.55; 95% CI, 1.27-9.92; P = .02). Conclusions and Relevance: Use of ioPTH is associated with higher cure rates for patients with primary hyperparathyroidism undergoing MIP. Minimally invasive parathyroidectomy performed without ioPTH is associated with less conversion to bilateral neck exploration at initial surgery but with lower cure rates and an increased risk for reoperation. Trial Registration: PROSPERO identifier: CRD42020148588.


Asunto(s)
Hiperparatiroidismo Primario/cirugía , Cuidados Intraoperatorios , Procedimientos Quirúrgicos Mínimamente Invasivos , Hormona Paratiroidea/administración & dosificación , Paratiroidectomía/métodos , Humanos
17.
Calcif Tissue Int ; 108(3): 391-406, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33170307

RESUMEN

To verify whether PTH acts on bone-specific blood vessels and on cells surrounding these blood vessels, 6-week-old male mice were subjected to vehicle (control group) or hPTH [1-34] (20 µg/kg/day, PTH group) injections for 2 weeks. Femoral metaphyses were used for histochemical and immunohistochemical studies. In control metaphyses, endomucin-positive blood vessels were abundant, but αSMA-reactive blood vessels were scarce. In the PTH-administered mice, the lumen of endomucin-positive blood vessels was markedly enlarged. Moreover, many αSMA-positive cells were evident near the blood vessels, and seemed to derive from those vessels. These αSMA-positive cells neighboring the blood vessels showed features of mesenchymal stromal cells, such as immunopositivity for c-kit and tissue nonspecific alkaline phosphatase (TNALP). Thus, PTH administration increased the population of perivascular/stromal cells positive for αSMA and c-kit, which were likely committed to the osteoblastic lineage. To understand the cellular events that led to increased numbers and size of bone-specific blood vessels, we performed immunohistochemical studies for PTH/PTHrP receptor and VEGF. After PTH administration, PTH/PTHrP receptor, VEGF and its receptor flk-1 were consistently identified in both osteoblasts and blood vessels (endothelial cells and surrounding perivascular cells). Our findings suggest that exogenous PTH increases the number and size of bone-specific blood vessels while fostering perivascular/stromal cells positive for αSMA/TNALP/c-kit.


Asunto(s)
Vasos Sanguíneos/crecimiento & desarrollo , Huesos , Hormona Paratiroidea/administración & dosificación , Células del Estroma/citología , Fosfatasa Alcalina/metabolismo , Animales , Huesos/irrigación sanguínea , Masculino , Ratones , Osteoblastos , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptor de Hormona Paratiroídea Tipo 1/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo
18.
Eur J Endocrinol ; 183(6): K13-K21, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33112267

RESUMEN

INTRODUCTION: Gain-of-function mutations in the CASR gene cause Autosomal Dominant Hypocalcemia Type 1 (ADH1), the most common genetic cause of isolated hypoparathyroidism. Subjects have increased calcium sensitivity in the renal tubule, leading to increased urinary calcium excretion, nephrocalcinosis and nephrolithiasis when compared with other causes of hypoparathyroidism. The traditional approach to treatment includes activated vitamin D but this further increases urinary calcium excretion. METHODS: In this case series, we describe the use of recombinant human parathyroid hormone (rhPTH)1-84 to treat subjects with ADH1, with improved control of serum and urinary calcium levels. RESULTS: We describe two children and one adult with ADH1 due to heterozygous CASR mutations who were treated with rhPTH(1-84). Case 1 was a 9.4-year-old female whose 24-h urinary calcium decreased from 7.5 to 3.9 mg/kg at 1 year. Calcitriol and calcium supplementation were discontinued after titration of rhPTH(1-84). Case 2 was a 9.5-year-old male whose 24-h urinary calcium decreased from 11.7 to 1.7 mg/kg at 1 year, and calcitriol was also discontinued. Case 3 was a 24-year-old female whose treatment was switched from multi-dose teriparatide to daily rhPTH(1-84). All three subjects achieved or maintained target serum levels of calcium and normal or improved urinary calcium levels with daily rhPTH(1-84) monotherapy. CONCLUSIONS: We have described three subjects with ADH1 who were treated effectively with rhPTH(1-84). In all cases, hypercalciuria improved by comparison to treatment with conventional therapy consisting of calcium supplementation and calcitriol.


Asunto(s)
Hipoparatiroidismo/tratamiento farmacológico , Hipoparatiroidismo/genética , Hormona Paratiroidea/administración & dosificación , Receptores Sensibles al Calcio/genética , Niño , Femenino , Humanos , Hipoparatiroidismo/diagnóstico , Masculino , Proteínas Recombinantes/administración & dosificación , Resultado del Tratamiento , Adulto Joven
19.
Curr Osteoporos Rep ; 18(5): 515-525, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32845464

RESUMEN

PURPOSE OF REVIEW: The skeletal system provides an important role to support body structure and protect organs. The complexity of its architecture and components makes it challenging to deliver the right amount of the drug into bone regions, particularly avascular cartilage lesions. In this review, we describe the recent advance of bone-targeting methods using bisphosphonates, polymeric oligopeptides, and nanoparticles on osteoporosis and rare skeletal diseases. RECENT FINDINGS: Hydroxyapatite (HA), a calcium phosphate with the formula Ca10(PO4)6(OH)2, is a primary matrix of bone mineral that includes a high concentration of positively charged calcium ion and is found only in the bone. This unique feature makes HA a general targeting moiety to the entire skeletal system. We have applied bone-targeting strategy using acidic amino acid oligopeptides into lysosomal enzymes, demonstrating the effects of bone-targeting enzyme replacement therapy and gene therapy on bone and cartilage lesions in inherited skeletal disorders. Virus or no-virus gene therapy using techniques of engineered capsid or nanomedicine has been studied preclinically for skeletal diseases. Efficient drug delivery into bone lesions remains an unmet challenge in clinical practice. Bone-targeting therapies based on gene transfer can be potential as new candidates for skeletal diseases.


Asunto(s)
Enfermedades Óseas/tratamiento farmacológico , Hipofosfatasia/tratamiento farmacológico , Mucopolisacaridosis IV/tratamiento farmacológico , Osteoporosis/tratamiento farmacológico , Fosfatasa Alcalina/administración & dosificación , Aminoácidos Acídicos , Conservadores de la Densidad Ósea/administración & dosificación , Calcitonina/administración & dosificación , Condroitinsulfatasas/administración & dosificación , Difosfonatos , Sistemas de Liberación de Medicamentos , Durapatita , Terapia de Reemplazo Enzimático , Humanos , Nanopartículas , Oligopéptidos , Hormona Paratiroidea/administración & dosificación
20.
J Clin Endocrinol Metab ; 105(10)2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32738041

RESUMEN

CONTEXT: Chronic hypoparathyroidism (HypoPT) is conventionally managed with oral calcium and active vitamin D. Recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) is a therapy targeting the pathophysiology of HypoPT by replacing parathyroid hormone. OBJECTIVE: To compare changes in the estimated glomerular filtration rate (eGFR) in patients with chronic HypoPT receiving or not receiving rhPTH(1-84) during a 5-year period. DESIGN/SETTING: A retrospective analysis of patients with chronic HypoPT treated with or without rhPTH(1-84). PATIENTS: Sixty-nine patients with chronic HypoPT from 4 open-label, long-term trials (NCT00732615, NCT01268098, NCT01297309, and NCT02910466) composed the rhPTH(1-84) cohort and 53 patients with chronic HypoPT not receiving rhPTH(1-84) from the Geisinger Healthcare Database (01/2004-06/2016) composed the historical control cohort. INTERVENTIONS: The rhPTH(1-84) cohort (N = 69) received rhPTH(1-84) therapy; the historical control cohort (N = 53) did not receive rhPTH(1-84). MAIN OUTCOME MEASURES: Changes in eGFR from baseline during a 5-year follow-up were examined in multivariate regression analyses. RESULTS: At baseline, demographic characteristics and eGFR were similar between cohorts, though the proportions with diabetes and cardiac disorders were lower in the rhPTH(1-84) cohort. At the end of follow-up, mean eGFR increased by 2.8 mL/min/1.73 m2 in the rhPTH(1-84) cohort, while mean eGFR fell by 8.0 mL/min/1.73 m2 in the control cohort. In the adjusted model, the difference in the annual eGFR change between the rhPTH(1-84) cohort and the control cohort was 1.7 mL/min/1.73 m2 per year (P = 0.009). CONCLUSIONS: Estimated glomerular filtration rate was preserved for over 5 years among patients with chronic HypoPT receiving rhPTH(1-84) treatment, contrasting with an eGFR decline among those not receiving rhPTH(1-84).


Asunto(s)
Tasa de Filtración Glomerular/efectos de los fármacos , Hipoparatiroidismo/tratamiento farmacológico , Hormona Paratiroidea/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Calcitriol/administración & dosificación , Calcio/administración & dosificación , Enfermedad Crónica/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular/fisiología , Humanos , Hidroxicolecalciferoles/administración & dosificación , Hipoparatiroidismo/fisiopatología , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes/administración & dosificación , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
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