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1.
Surg Endosc ; 36(9): 6984-6996, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35226161

RESUMEN

BACKGROUND: Bariatric surgery has been shown to result in weight loss, improved hemoglobin A1C, and decreased mortality but can also lead to bone loss and increased fracture rates. Serum IGFBP-2 is elevated in patients after bariatric surgery and although it may lead to improved blood glucose, may also drive bone resorption, and inhibit IGF-I action. This study tested the hypothesis that Igfbp2-/- mice were acutely protected from bone loss after vertical sleeve gastrectomy (VSG). METHODS: Thirty-four mice, 17 Igfbp2-/- and 17 + / + underwent a hand-sewn VSG or sham surgery, at 16 weeks of age. Mice were harvested at 20 weeks of age. DXA was measured for body composition, areal bone mineral density (aBMD), areal bone mineral content (aBMC), femoral bone mineral density (fBMD), and femoral bone mineral content (fBMC) at 15, 18, and 20 weeks of age. Micro-computed tomography and serum ELISA assays were measured and analyzed at 20 weeks of age. RESULTS: Both Igfbp2-/- and + / + mice lost significant weight (P = 0.0251, P = 0.0003, respectively) and total fat mass (P = 0.0082, P = 0.0004, respectively) at 4 weeks after VSG. Igfbp2+/+ mice lost significant aBMD, fBMD, fBMC, trabecular BMD, trabecular BV/TV and cortical tissue mineral density (P = 0.0150, P = 0.0313, P = 0.0190, P = 0.0072, and 0.0320 respectively). The Igfbp2-/- mice did not show significant bone loss in these parameters nor in trabecular BV/TV. Both Igfbp2-/- and + / + mice had less cortical bone area (P = 0.0181, P = < .00001), cortical area over total area (P = 0.0085, P = 0.0007), and cortical thickness (P = 0.0050, P = < 0.0001), respectively. Igfbp2+/+ mice demonstrated significantly lower polar, minimum, and maximum moments of inertia (P = 0.0031, P = 0.0239, and P = 0.0037, respectively). Igfbp2+/+ had significantly higher levels of IGFBP-2 at 2 weeks postoperatively after VSG (P = 0.035), and elevated levels of CTx and P1NP (P = 0.0127, P = 0.0058, respectively). CONCLUSIONS: Igfbp2-/- mice were protected against trabecular bone loss and had attenuated cortical bone loss 4 weeks after VSG.


Asunto(s)
Hueso Esponjoso , Gastrectomía/efectos adversos , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina , Osteoporosis/genética , Animales , Densidad Ósea , Hueso Esponjoso/diagnóstico por imagen , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Ratones , Osteoporosis/patología , Microtomografía por Rayos X
2.
Nat Commun ; 12(1): 6271, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34725346

RESUMEN

Some osteoblasts embed within bone matrix, change shape, and become dendrite-bearing osteocytes. The circuitry that drives dendrite formation during "osteocytogenesis" is poorly understood. Here we show that deletion of Sp7 in osteoblasts and osteocytes causes defects in osteocyte dendrites. Profiling of Sp7 target genes and binding sites reveals unexpected repurposing of this transcription factor to drive dendrite formation. Osteocrin is a Sp7 target gene that promotes osteocyte dendrite formation and rescues defects in Sp7-deficient mice. Single-cell RNA-sequencing demonstrates defects in osteocyte maturation in the absence of Sp7. Sp7-dependent osteocyte gene networks are associated with human skeletal diseases. Moreover, humans with a SP7R316C mutation show defective osteocyte morphology. Sp7-dependent genes that mark osteocytes are enriched in neurons, highlighting shared features between osteocytic and neuronal connectivity. These findings reveal a role for Sp7 and its target gene Osteocrin in osteocytogenesis, revealing that pathways that control osteocyte development influence human bone diseases.


Asunto(s)
Enfermedades Óseas/metabolismo , Dendritas/metabolismo , Proteínas Musculares/metabolismo , Osteocitos/metabolismo , Factor de Transcripción Sp7/metabolismo , Factores de Transcripción/metabolismo , Adolescente , Animales , Enfermedades Óseas/genética , Enfermedades Óseas/fisiopatología , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Musculares/genética , Mutación , Factor de Transcripción Sp7/genética , Factores de Transcripción/genética
3.
Semin Nephrol ; 41(2): 168-179, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-34140095

RESUMEN

Bone disease after kidney transplantation is associated with an increased risk of fractures, morbidity, and mortality. Its pathophysiology is complex, involving multiple contributors including pretransplant bone disease, immunosuppressive medications, and changes in the parathyroid-bone-kidney axis. Risk scores, bone turnover markers, and noninvasive imaging modalities are only able to partially predict the fracture risk in kidney transplant recipients. The optimal management of bone disease after kidney transplantation has not yet been established, with only a limited number of randomized clinical trials evaluating the efficacy of treatment regimens in kidney transplant recipients. This review focuses on the pathophysiology, evaluation, prevention, and treatment of post-kidney transplant mineral and bone disease as guided by recent evidence.


Asunto(s)
Enfermedades Óseas , Fracturas Óseas , Trasplante de Riñón , Densidad Ósea , Enfermedades Óseas/etiología , Humanos , Minerales
4.
J Clin Invest ; 129(12): 5187-5203, 2019 12 02.
Artículo en Inglés | MEDLINE | ID: mdl-31430259

RESUMEN

The parathyroid hormone 1 receptor (PTH1R) mediates the biologic actions of parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP). Here, we showed that salt-inducible kinases (SIKs) are key kinases that control the skeletal actions downstream of PTH1R and that this GPCR, when activated, inhibited cellular SIK activity. Sik gene deletion led to phenotypic changes that were remarkably similar to models of increased PTH1R signaling. In growth plate chondrocytes, PTHrP inhibited SIK3, and ablation of this kinase in proliferating chondrocytes rescued perinatal lethality of PTHrP-null mice. Combined deletion of Sik2 and Sik3 in osteoblasts and osteocytes led to a dramatic increase in bone mass that closely resembled the skeletal and molecular phenotypes observed when these bone cells express a constitutively active PTH1R that causes Jansen's metaphyseal chondrodysplasia. Finally, genetic evidence demonstrated that class IIa histone deacetylases were key PTH1R-regulated SIK substrates in both chondrocytes and osteocytes. Taken together, our findings establish that SIK inhibition is central to PTH1R action in bone development and remodeling. Furthermore, this work highlights the key role of cAMP-regulated SIKs downstream of GPCR action.


Asunto(s)
Desarrollo Óseo , Remodelación Ósea , Hormona Paratiroidea/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor de Hormona Paratiroídea Tipo 1/metabolismo , Animales , Animales Recién Nacidos , Proliferación Celular , Condrocitos/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Eliminación de Gen , Hipertrofia , Masculino , Ratones , Ratones Noqueados , Mutación , Osteoblastos/metabolismo , Osteocitos/metabolismo , Fosforilación , Proteínas Tirosina Quinasas/metabolismo , Transcriptoma
5.
Science ; 358(6367)2017 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-29191879

RESUMEN

Bone marrow-derived myeloid cells can accumulate within tumors and foster cancer outgrowth. Local immune-neoplastic interactions have been intensively investigated, but the contribution of the systemic host environment to tumor growth remains poorly understood. Here, we show in mice and cancer patients (n = 70) that lung adenocarcinomas increase bone stromal activity in the absence of bone metastasis. Animal studies reveal that the cancer-induced bone phenotype involves bone-resident osteocalcin-expressing (Ocn+) osteoblastic cells. These cells promote cancer by remotely supplying a distinct subset of tumor-infiltrating SiglecFhigh neutrophils, which exhibit cancer-promoting properties. Experimentally reducing Ocn+ cell numbers suppresses the neutrophil response and lung tumor outgrowth. These observations posit osteoblasts as remote regulators of lung cancer and identify SiglecFhigh neutrophils as myeloid cell effectors of the osteoblast-driven protumoral response.


Asunto(s)
Adenocarcinoma/patología , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Huesos/patología , Lectinas/metabolismo , Neoplasias Pulmonares/patología , Infiltración Neutrófila , Neutrófilos/metabolismo , Neutrófilos/patología , Osteoblastos/patología , Adenocarcinoma del Pulmón , Animales , Densidad Ósea , Células de la Médula Ósea/patología , Huesos/metabolismo , Línea Celular Tumoral , Humanos , Ratones , Ratones Endogámicos C57BL , Células Mieloides/patología , Neoplasias Experimentales/patología , Osteocalcina/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo
6.
PLoS One ; 12(7): e0180387, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28719612

RESUMEN

BACKGROUND: Observational studies have shown a beneficial effect of obesity on bone health; however, most of those studies were not based on bone biopsies. Metabolic syndrome (MetS) could have an effect on bone remodeling. However, there are no data on the effects of MetS in the presence of renal osteodystrophy. OBJECTIVE: The aim of this study was to investigate associations between MetS and renal osteodystrophy using the bone histomorphometric turnover-mineralization-volume (TMV) classification. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: This observational cross-sectional study included 55 hemodialysis patients (28 women/27 men) who were evaluated for MetS and bone histomorphometry. Biochemical parameters included calcium, phosphorus, alkaline phosphatase, intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, free serum leptin, fibroblast growth factor 23 (FGF23), intact osteocalcin, sclerostin (Scl), glucose, insulin, and thyroid hormones. Robust models of multivariate linear regressions were used for the statistical analyses. RESULTS: Females had higher iPTH levels (1,143 vs. 358, p = 0.02). Patients with normal bone volume (BV/TV) had a higher prevalence of MetS (73.6% vs. 41.7%, p = 0.02) and higher serum phosphorus, C-terminal FGF23 and insulin levels. The multivariate regression analysis showed that low-density lipoprotein cholesterol (LDL) was positively correlated with bone formation rate (BFR/BS) and negatively associated with mineralization lag time. Bone volume was negatively associated with age but positively associated with MetS. Body mass index (BMI) was not correlated with any of the bone histomorphometric parameters. CONCLUSION: Our results suggest that MetS is not a risk factor for low bone volume in hemodialysis patients. Furthermore, BMI alone was not related to bone volume in this population.


Asunto(s)
Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/complicaciones , Síndrome Metabólico/complicaciones , Obesidad/complicaciones , Proteínas Adaptadoras Transductoras de Señales , Adulto , Anciano , Densidad Ósea , Proteínas Morfogenéticas Óseas/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/fisiopatología , Estudios Transversales , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Marcadores Genéticos , Humanos , Resistencia a la Insulina , Leptina/sangre , Masculino , Persona de Mediana Edad , Osteocalcina/sangre
7.
Calcif Tissue Int ; 97(4): 421-5, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26108650

RESUMEN

Pregnancy and lactation-associated osteoporosis (PAO) is a rare condition with little known pathophysiology. Most cases are diagnosed in the third trimester of pregnancy or in the first weeks postpartum, particularly in first pregnancies. Vertebral fractures are most commonly observed and characterised by prolonged severe pain, functional limitations and a loss of height. Measurements of bone mineral density and biochemical markers of bone remodelling are the clinical methods most commonly used for the management of these patients. However, a bone biopsy with histomorphometric analysis has been considered to be the gold-standard. Few studies have evaluated the histomorphometry in patients with this clinical condition and none of them performed the procedure at the beginning of the clinical assessment. In this study, we report a case of PAO in a 31-year-old postpartum patient who had undergone a twin pregnancy. We describe the clinical, laboratory tests and imaging features. Bone histomorphometry showed a high resorption rate and excellent evolution after 1 year of treatment with intravenous zoledronic acid. Our data suggest that osteoclastogenesis plays a central role in the pathophysiological processes of this disease.


Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Lactancia Materna/efectos adversos , Difosfonatos/uso terapéutico , Imidazoles/uso terapéutico , Osteoporosis/tratamiento farmacológico , Adulto , Densidad Ósea , Femenino , Humanos , Lactancia , Osteoporosis/etiología , Osteoporosis/fisiopatología , Embarazo , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/fisiopatología , Ácido Zoledrónico
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