Marked alterations in the structure, dynamics and maturation of growth plate likely explain growth retardation and bone deformities of young Hyp mice

Fuente, Rocío Aller de la; Gil‐Peña, Helena; Claramunt-Taberner, Débora; Hernández-Frías, Olaya; Fernández-Iglesias, Ángela; Hermida-Prado, Francisco; Anes-González, Gonzalo; Rubio‐Aliaga, Isabel; López, José M.; Santos, Fernando

doi:10.1016/j.bone.2018.08.004

Cited by 23 publications

(26 citation statements)

References 36 publications

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“…Bone resorption was evaluated by tartrate‐resistant acid phosphatase (TRAP) and alkaline phosphatase (ALP) activity. TRAP and ALP were determined in left tibiae as described previously 32 . TRAP assay was used to quantify the number of active osteoclasts as the number of TRAP‐positive cells per 100 µm 2 along the ossification front.…”

Section: Methodsmentioning

confidence: 99%

Systemic Jak1 activation causes extrarenal calcitriol production and skeletal alterations provoking stunted growth

et al. 2021

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Mineral homeostasis is regulated by a complex network involving endocrine actions by calcitriol, parathyroid hormone (PTH), and FGF23 on several organs including kidney, intestine, and bone. Alterations of mineral homeostasis are found in chronic kidney disease and other systemic disorders. The interplay between the immune system and the skeletal system is not fully understood, but cytokines play a major role in modulating calcitriol production and function. One of the main cellular signaling pathways mediating cytokine function is the Janus kinase (JAK)––signal transducer and activator of transcription (STAT) pathway. Here, we used a mouse model (Jak1S645P+/−) that resembles a constitutive activating mutation of the Jak1/Stat3 signaling pathway in humans, and shows altered mineral metabolism, with higher fibroblast growth factor 23 (FGF23) levels, lower PTH levels, and higher calcitriol levels. The higher calcitriol levels are probably due to extrarenal calcitriol production. Furthermore, systemic Jak1/Stat3 activation led to growth impairment and skeletal alterations. The growth plate in long bones showed decreased chondrocyte proliferation rates and reduced height of terminal chondrocytes. Furthermore, we demonstrate that Jak1 is also involved in bone remodeling early in life. Jak1S645P+/− animals have decreased bone and cortical volume, imbalanced bone remodeling, reduced MAP kinase signaling, and local inflammation. In conclusion, Jak1 plays a major role in bone health probably both, directly and systemically by regulating mineral homeostasis. Understanding the role of this signaling pathway will contribute to a better knowledge in bone growth and in mineral physiology, and to the development of selective Jak inhibitors as osteoprotective agents.

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Section: Methodsmentioning

confidence: 99%

Systemic Jak1 activation causes extrarenal calcitriol production and skeletal alterations provoking stunted growth

et al. 2021

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“…The left tibias, fixed in 4% paraformaldehyde (PFA) and embedded in methyl methacrylate [ 35 ], were used for the histological and inmunofluorescence analyses.…”

Section: Methodsmentioning

confidence: 99%

Innovative Three-Dimensional Microscopic Analysis of Uremic Growth Plate Discloses Alterations in the Process of Chondrocyte Hypertrophy: Effects of Growth Hormone Treatment

Fernández-Iglesias

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Gil‐Peña

et al. 2020

IJMS

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Chronic kidney disease (CKD) alters the morphology and function of the growth plate (GP) of long bones by disturbing chondrocyte maturation. GP chondrocytes were analyzed in growth-retarded young rats with CKD induced by adenine intake (AD), control rats fed ad libitum (C) or pair-fed with the AD group (PF), and CKD rats treated with growth hormone (ADGH). In order to study the alterations in the process of GP maturation, we applied a procedure recently described by our group to obtain high-quality three-dimensional images of whole chondrocytes that can be used to analyze quantitative parameters like cytoplasm density, cell volume, and shape. The final chondrocyte volume was found to be decreased in AD rats, but GH treatment was able to normalize it. The pattern of variation in the cell cytoplasm density suggests that uremia could be causing a delay to the beginning of the chondrocyte hypertrophy process. Growth hormone treatment appears to be able to compensate for this disturbance by triggering an early chondrocyte enlargement that may be mediated by Nkcc1 action, an important membrane cotransporter in the GP chondrocyte enlargement.

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“…The mechanism responsible for growth impairment in XLH remains to be elucidated. It has been suggested that both cartilage and bone alterations are important underlying causes for the impaired growth and long bone deformities observed in XLH [63]. Moreover, studies using murine models of XLH indicated that antagonising FGF23 activity, by administering a mitogen-activated protein kinase (MAPK) pathway inhibitor, resulted not only in the acceleration of growth and improvement of rickets, but also in a normalisation of growth plate structure [64].…”

Section: Growth Retardation In Xlhmentioning

confidence: 99%

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2021

Int J Rare Dis Disord

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The human skeleton is composed of bone, a living tissue that undergoes constant development throughout life. It is well established that changes in bone metabolism during the developmental stages of growth, modelling and remodelling determine long-lasting physiological parameters, such as final height achieved, peak bone mass, bone quality and bone health. A complex interplay of environmental, genetic, nutritional, physiological and behavioural factors plays a role in these processes. These modifiable and non-modifiable factors influence skeletal development and bone quality, as well as the occurrence of clinical conditions during adulthood, such as osteoarthritis and osteoporosis.

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Marked alterations in the structure, dynamics and maturation of growth plate likely explain growth retardation and bone deformities of young Hyp mice

Cited by 23 publications

References 36 publications

Systemic Jak1 activation causes extrarenal calcitriol production and skeletal alterations provoking stunted growth

Systemic Jak1 activation causes extrarenal calcitriol production and skeletal alterations provoking stunted growth

Innovative Three-Dimensional Microscopic Analysis of Uremic Growth Plate Discloses Alterations in the Process of Chondrocyte Hypertrophy: Effects of Growth Hormone Treatment

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