Targeted Limb Heating Augments the Actions of IGF1 in the Growth Plate and Increases Bone Elongation in Growing Mice

Bone elongation disorders can lead to painful musculoskeletal disabilities in adulthood. Existing treatment options to correct left-right asymmetry in limb length include invasive surgeries and/or drug regimens. These are often only partially effective. Previous studies in weanling mice have shown that a daily application of mild heat (40°C) to limbs on one side of the body could be used to noninvasively enhance bone elongation. However, the impact of heat-treatment on bone at the cellular level remains elusive. The epiphyseal growth plate, the band of cartilage located at each end of long bones, is the main site of longitudinal growth and is regulated by local and systemic growth factors. Insulin-like growth factor 1 (IGF1) is the major regulator of growth and controls bone elongation by promoting chondrocyte proliferation and hypertrophy. The objective of this study was to build upon an established method of targeted limb heating to determine how heat-treatment influences IGF1 action in the growth plate. This study tests the hypothesis that exposure to warm temperature augments the actions of IGF1 in the growth plate and permanently increases length of the extremities. This dissertation demonstrates that differences of less than 1.5% are functionally significant measured by a nearly 20% increase in hindlimb weight bearing on heat-treated sides. Heat-enhanced bone elongation is documented in female C57BL/6 mice after 7 days of heat-treatment during the most active period of growth from 3-4 weeks of age. This increase in bone elongation is accompanied by increased chondrocyte proliferation and hypertrophy in the proximal tibial growth plate. Moreover, this study is the first to show that targeted limb-heating impacts local action of IGF1 in growth plate chondrocytes. Results suggest that heat-induced limb length is IGF1 dependent since the growth effects are attenuated when IGF1 activity is blocked. Administration of a low dose of IGF1 (2.5mg/kg) was found to augment heat enhanced bone elongation and effects were sustained to skeletal maturity (12 weeks of age). These studies help contribute to the ultimate goal of developing a noninvasive method for lengthening bones that may translate in a clinical setting to treat linear growth disorders in children

GH and the cardiovascular system: an update on a topic at heart

In this review, the importance of growth hormone (GH) for the maintenance of normal cardiac function in adult life is discussed. Physiological effects of GH and underlying mechanisms for interactions between GH and insulin-like growth factor I (IGF-I) and the cardiovascular system are covered as well as the cardiac dysfunction caused both by GH excess (acromegaly) and by GH deficiency in adult hypopituitary patients. In both acromegaly and adult GH deficiency, there is also increased cardiovascular morbidity and mortality possibly linked to aberrations in GH status. Finally, the status of the GH/IGF-I system in relation to heart failure and the potential of GH as a therapeutic tool in the treatment of heart failure are reviewed in this article. © 2014 The Author(s)

Proteasen sind essentielle Faktoren in der Kontrolle der Spätdifferenzierung von Chondrozyten während der Knochenbildung

Während der endochondralen Ossifikation wird Knochengewebe aus einer Anlage aus Knorpel gebildet. Diesem Ersatz des einen Gewebetyps durch einen anderen geht eine Reihe von Prozessen voraus, die als Chondrozytenspätdifferenzierung bezeichnet wird. Diese wird sowohl durch Proteasen, Vitamin D, als auch durch die ECM beeinflusst. Die Chondrozytenspätdifferenzierung ist ein negativ regulierter Prozess. Diese Blockade wird bei der Knochensynthese aufgehoben. Bei der Osteoarthrose findet pathologischer Weise ebenfalls eine Deblockade der Spätdifferenzierung statt, die eine Degeneration der Knorpeligen Anteile der Gelenke zur Folge hat. Somit sollten Erkenntnisse über die genauen Mechanismen der Deblockade, physiologisch bei der enchondralen Ossifikation, pathologisch bei der Osteoarthrose, Aufschlüsse über den Pathomechanismus der Osteoarthrose liefern

Estudo da placa de crescimento após um estímulo nóxico num modelo experimental de crescimento de recuperação.

MedicinaDoctoral Programme in Medicin

The role of suppressor of cytokine signalling-2 in endochondral bone growth

Suppressor of Cytokine Signalling-2 (SOCS2) is a negative regulator of growth hormone (GH) signalling and bone growth via inhibition of the JAK/STAT pathway. This has been classically demonstrated by the overgrowth phenotype of SOCS2-/- mice which have normal systemic IGF-1 levels. The local effects of GH on bone growth are equivocal and therefore this study aimed to understand better the SOCS2 signalling mechanisms mediating the local actions on epiphyseal chondrocytes and bone growth. SOCS2, in contrast to SOCS1 and SOCS3 expression, was increased in cultured chondrocytes following GH challenge; and gain-and-loss of function studies indicated that SOCS2 acts to negatively regulate GH stimulated chondrocyte STAT phosphorylation. This was confirmed by the observation that GH stimulates the longitudinal growth of cultured SOCS2-/- embryonic metatarsals and the proliferation of chondrocytes within. Consistent with this; bone growth rates, growth plate zone widths and chondrocyte proliferation were all increased in 6-week old SOCS2-/- mice as was the number of phosphorylated STAT-5 positive hypertrophic chondrocytes. The results of these studies indicate that the SOCS2-/- mouse represents a valid model for studying the local effects of GH and IGF-1 on bone growth. Chronic paediatric inflammatory diseases are well accepted to lead to growth retardation and this is likely due to raised inflammatory cytokine levels and reduced GH/IGF-1 signalling. Whilst SOCS2 was not found to be increased in response to inflammatory cytokines, SOCS2-/- mice were protected from LPS-induced growth retardation indicating that SOCS2 antagonists may help ameliorate the negative effects of chronic inflammation on growth

Hormona de crecimiento, destete y estado nutritivo

The GH-IGF-I system constitutes the major determinant of body size, specially in postnatal growth. It is well established that exogenous GH increases muscle mass and decreases lipid content, leading to the alteration of nutrients repartitioning. The mechanism involves, at least, an increase in the protein synthesis and creates a status of positive nitrogen balance by increasing nitrogen retention and decreasing protein catabolism in animals fed an adequate diet. GH can act directly on tissues inducing these metabolic changes and can also stimulate IGF-I in an endocrine, autocrine or paracrine fashion. Body fat decreases by the increase of triglycerides hydrolysis and the decrease of free fatty acid re-esterification. The magnitude of the response to exogenous GH is variable and at least partly attributable to the nutritional status and to the growth stage of animal. The action of growth hormone is minimal between the 2nd and the 3rd week of age and is manifested at 31 days of age, increasing its efficacy at puberty. The reason for this refractoriness to GH treatment is unknown but it can be related to the biphasic response developed in mice fed two dietary protein levels between 21 to 50 days of age, when administered with rhGH. The GH-induced fall of feed intake in mice between 21 and 30 days old provokes a loss of body and skeletal muscle components due to the lack of nutrients leading to the impairment of growth. Later on (35-50 days) the self-controlled increase of feed intake let the recovery of the body weight, through of a catch-up growth phenomenon, characterized by a higher lipid body accretion, similar to the compensatory growth developed during refeeding after protein-energy malnutrition, and possibly contemporary of a GH-resistance status of the fat mass. However, the GH anabolic action is clearly seen on the muscle mass, specially in the well-nourished mice, with increased fractional protein synthesis rate that allows higher both muscle protein deposit and muscle cellular size. Thus, GH administration throughout weaning seems to interfere with the delicate adaptive mechanisms to the solid diet, impeding normal growth bet ween the 3rd and 4th week of age and inducing a compensatory growth from 35 days of age.El eje GH-IGF-I es el regulador fundamental del crecimiento postnatal y el determinante del tamaño corporal. El tratamiento con GH aumenta la masa muscular y disminuye el depósito graso, modificando la redistribución de los depósitos corporales. Por su capacidad de aumentar la síntesis y de disminuir el catabolismo proteico genera un balance nitrogenado positivo, bien actuando directamente a nivel tisular o mediante la acción endocrina, paracrina o autocrina del factor IGF-I. De forma paralela, la hormona somatotropa incrementa la hidrólisis de los triglicéridos y disminuye la lipogénesis. Esta respuesta metabólica a la GH exógena varía con diversos factores, entre los que destacan el nivel nutritivo y la etapa de crecimiento del animal. Se conoce por una parte, que la acción somatotropa requiere de un aporte suficiente de nutrientes en la dieta y por otra, que sus efectos son mínimos entre la segunda y tercera semana de crecimiento postnatal, aumentando su eficacia entre los 31 días de vida y la pubertad. Aunque no se conoce la causa de esta refractoriedad al tratamiento con GH en estas primeras etapas de la vida, podría estar relacionada con la respuesta bifásica a la GH, desarrollada en ratones BALB/c machos rhGH-tratados entre los 21 y 50 días de vida y alimentados con dos concentraciones de proteína en la dieta (12 y 20%). La hipofagia GHinducida entre los 21 y 30 días de vida es la causa primordial del estado de subnutrición que aparece en estos animales y que da lugar a la detención del crecimiento por falta de sustratos, eliminando la acción anabólica de la hormona. Posteriormente, el incremento autorregulado de la ingesta favorece la recuperación del crecimiento entre los 35 y 50 días de vida, periodo en el que se desarrolla un crecimiento de carácter compensador, caracterizado por un acúmulo excesivo de la masa grasa, similar al determinado por el crecimiento que sigue a la realimentación después de malnutrición, lo que puede coexistir con un estado de resistencia del tejido adiposo a la GH. Sin embargo el efecto anabólico de la somatotropa parece manifestarse, en los animales bien nutridos, por un mayor depósito de la proteína muscular al incrementar la tasa fraccional de síntesis proteica, que permite la aparición de un fenómeno de hipertrofia compensadora. Por lo tanto, la administración de rhGH en el momento del destete parece interferir con los delicados mecanismos de adaptación a la alimentación sólida característicos de este periodo, e inducir el cese del crecimiento entre los 21 y 30 días, generando más tarde un crecimiento de carácter compensador que se inicia a partir de los 35 días de vida