scholarly journals The JAK1/STAT3/SOCS3 axis in bone development, physiology, and pathology

2020 ◽  
Vol 52 (8) ◽  
pp. 1185-1197 ◽  
Author(s):  
Natalie A. Sims
Keyword(s):  
Bone Growth ◽  
Bone Structure ◽  
Bone Development ◽  
Osteoclast Formation ◽  
Bone Lengthening ◽  
Growth Plate Chondrocytes ◽  
Paracrine Factors ◽  
Stat3 Signaling ◽  
Skeletal Defects ◽  
Normal Differentiation

Abstract Bone growth and the maintenance of bone structure are controlled by multiple endocrine and paracrine factors, including cytokines expressed locally within the bone microenvironment and those that are elevated, both locally and systemically, under inflammatory conditions. This review focuses on those bone-active cytokines that initiate JAK–STAT signaling, and outlines the discoveries made from studying skeletal defects caused by induced or spontaneous modifications in this pathway. Specifically, this review describes defects in JAK1, STAT3, and SOCS3 signaling in mouse models and in humans, including mutations designed to modify these pathways downstream of the gp130 coreceptor. It is shown that osteoclast formation is generally stimulated indirectly by these pathways through JAK1 and STAT3 actions in inflammatory and other accessory cells, including osteoblasts. In addition, in bone remodeling, osteoblast differentiation is increased secondary to stimulated osteoclast formation through an IL-6-dependent pathway. In growth plate chondrocytes, STAT3 signaling promotes the normal differentiation process that leads to bone lengthening. Within the osteoblast lineage, STAT3 signaling promotes bone formation in normal physiology and in response to mechanical loading through direct signaling in osteocytes. This activity, particularly that of the IL-6/gp130 family of cytokines, must be suppressed by SOCS3 for the normal formation of cortical bone.

Bone and muscle development in three inbred female mouse strains

2021 ◽  
Author(s):  
Ursula Föger-Samwald ◽  
Maria Papageorgiou ◽  
Katharina Wahl-Figlash ◽  
Katharina Kerschan-Schindl ◽  
Peter Pietschmann
Keyword(s):  
Trabecular Bone ◽  
Muscle Development ◽  
Bone Growth ◽  
Volume Fraction ◽  
Bone Structure ◽  
Bone Development ◽  
Mouse Strains ◽  
Structural Reorganization ◽  
Bone Volume Fraction ◽  
Trabecular Thickness

AbstractMuscle force is thought to be one of the main determinants of bone development. Hence, peak muscle growth is expected to precede peak bone growth. In this study, we investigated muscle and bone development in female C57BL/6 J, DBA/2JRj, and C3H/HeOuJ mice. Femoral cortical and trabecular bone structure and the weights of selected muscles were assessed at the ages of 8, 16, and 24 weeks. Muscle mass increased from 8 to 24 weeks in all 3 strains, suggesting peak muscle development at 24 weeks or later. Bone volume fraction, trabecular number, and connectivity density of the femur decreased or remained unchanged, whereas trabecular density and trabecular thickness largely increased. These results suggest a peak in trabecular bone accrual at 8 weeks or earlier followed by further increases in density and structural reorganization of trabeculae. Cortical density, cortical thickness, and cortical cross sectional area increased over time, suggesting a peak in cortical bone accrual at 24 weeks or later. In conclusion, our data provide evidence that growth of muscle lags behind trabecular bone accrual.

scholarly journals Reconstitution of the host holobiont in germ-free rats acutely increases bone growth and affects marrow cellular content

2020 ◽  
Author(s):  
PJ Czernik ◽  
RM Golonka ◽  
S Chakraborty ◽  
BS Yeoh ◽  
A Abokor ◽  
...  
Keyword(s):  
Bone Growth ◽  
Serum Levels ◽  
Short Chain Fatty Acids ◽  
Male Rats ◽  
Bone Lengthening ◽  
Mineral Density ◽  
Growth Plate Chondrocytes ◽  
Germ Free ◽  
Hepatic Expression ◽  
Short Term Exposure

AbstractIn recent years there has been growing evidence regarding the effect of microbiota on the skeletal growth and homeostasis. Here we present, for the first time, accelerated longitudinal and radial bone growth in young (7-week-old) germ-free male rats after short-term exposure to a newly established gut microbiota. Changes in bone mass and structure were analyzed after 10 days following the onset of colonization through cohousing with conventional rats and revealed unprecedented acceleration of bone accrual in cortical and trabecular compartments, increased bone tissue mineral density, improved proliferation and hypertrophy of growth plate chondrocytes, bone lengthening, and preferential deposition of periosteal bone in tibia diaphysis. In addition, the number of small-in-size adipocytes increased, while the number of megakaryocytes decreased, in the bone marrow of conventionalized germ-free rats. The observed changes in bone status were paralleled with a positive shift in microbiota composition towards short chain fatty acids (SCFA)-producing microbes, which reflected a dramatic increase in cecal concentration of SCFA, specifically butyrate. Further, reconstitution of the host holobiont increased hepatic expression of IGF-1 and its circulating levels, implicating an involvement of the somatotropic axis. Increased serum levels of 25-hydroxy vitamin D and alkaline phosphatase pointed toward an active process of bone formation. The acute stimulatory effect on bone growth occurred independently of body mass increase and resembled reversal of dysbiosis in adolescence, which is marked by rapid skeletal expansion. These findings may help in developing microbiota-based therapeutics to combat bone related disorders resulting from hormonal defects and/or malnutrition in children and adolescence.

scholarly journals Cartilage Ablation of Sirt1 Causes Inhibition of Growth Plate Chondrogenesis by Hyperactivation of mTORC1 Signaling

Endocrinology ◽  
2019 ◽  
Vol 160 (12) ◽  
pp. 3001-3017 ◽  
Author(s):  
Xinxin Jin ◽  
Xiaomin Kang ◽  
Liting Zhao ◽  
Mao Xu ◽  
Tianping Xie ◽  
...  
Keyword(s):  
Growth Plate ◽  
Growth Retardation ◽  
Bone Growth ◽  
Bone Development ◽  
Conditional Knockout ◽  
Negative Regulator ◽  
Sirtuin 1 ◽  
Growth Plate Chondrocytes ◽  
Mtorc1 Signaling

Abstract A growing body of evidence implies a pivotal role of sirtuin-1 (Sirt1) in chondrocyte function and homeostasis; however, its underlying mechanisms mediating chondrogenesis, which is an essential process for physiological skeletal growth, are still poorly understood. In the current study, we generated TamCartSirt1−/− [Sirt1 conditional knockout (cKO)] mice to explore the role of Sirt1 during postnatal endochondral ossification. Compared with control mice, cKO mice exhibited growth retardation associated with inhibited chondrocyte proliferation and hypertrophy, as well as activated apoptosis. These effects were regulated by hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) signaling, and thereby inhibition of autophagy and induction of endoplasmic reticulum stress in growth plate chondrocytes. IP injection of the mTORC1 inhibitor rapamycin to mice with Sirt1 deletion partially neutralized such inhibitory effects of Sirt1 ablation on longitudinal bone growth, indicating the causative link between SIRT1 and mTORC1 signaling in the growth plate. Mechanistically, SIRT1 interacted with tuberous sclerosis complex 2 (TSC2), a key upstream negative regulator of mTORC1 signaling, and loss of Sirt1 inhibited TSC2 expression, resulting in hyperactivated mTORC1 signaling in chondrocytes. In conclusion, our findings suggest that loss of Sirt1 may trigger mTORC1 signaling in growth plate chondrocytes and contributes to growth retardation, thus indicating that SIRT1 is an important regulator during chondrogenesis and providing new insights into the clinical potential of SIRT1 in bone development.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: Bone marrow adiposity and bone, a bad romance?

2018 ◽  
Vol 179 (4) ◽  
pp. R165-R182 ◽  
Author(s):  
Tareck Rharass ◽  
Stéphanie Lucas
Keyword(s):  
Bone Marrow ◽  
Bone Growth ◽  
Bone Marrow Cells ◽  
Adult Life ◽  
Osteoclast Formation ◽  
Childhood And Adolescence ◽  
Primary Osteoporosis ◽  
Mineral Density ◽  
Paracrine Factors ◽  
Haematopoietic Tissue

Bone marrow adipocytes (BMA-) constitute an original and heterogeneous fat depot whose development appears interlinked with bone status throughout life. The gradual replacement of the haematopoietic tissue by BMA arises in a well-ordered way during childhood and adolescence concomitantly to bone growth and continues at a slower rate throughout the adult life. Importantly, BM adiposity quantity is found well associated with bone mineral density (BMD) loss at different skeletal sites in primary osteoporosis such as in ageing or menopause but also in secondary osteoporosis consecutive to anorexia nervosa. Since BMA and osteoblasts originate from a common mesenchymal stem cell, adipogenesis is considered as a competitive process that disrupts osteoblastogenesis. Besides, most factors secreted by bone and bone marrow cells (ligands and antagonists of the WNT/β-catenin pathway, BMP and others) reciprocally regulate the two processes. Hormones such as oestrogens, glucocorticoids, parathyroid and growth hormones that control bone remodelling also modulate the differentiation and the activity of BMA. Actually, BMA could also contribute to bone loss through the release of paracrine factors altering osteoblast and/or osteoclast formation and function. Based on clinical and fundamental studies, this review aims at presenting and discussing these current arguments that support but also challenge the involvement of BMA in the bone mass integrity.

Human Transitions

2018 ◽  
pp. 206-238
Author(s):  
James H. Gosman ◽  
David A. Raichlen ◽  
Timothy M. Ryan
Keyword(s):  
Trabecular Bone ◽  
Bone Growth ◽  
Bone Structure ◽  
Bone Development ◽  
Skeletal Morphology ◽  
Behavior Understanding ◽  
Age Related ◽  
Microct Imaging ◽  
And Behavior ◽  
Bone Research

The analysis of cortical and trabecular bone development morphology offers a lens through which general biological processes of skeletal ontogeny can be viewed. These, in turn, establish a foundation upon which biocultural reconstructions of childhood can proceed. In this chapter, the authors draw on skeletal data generated by their systematic cortical and trabecular bone research agenda from a Norris Farms’ archaeological skeletal collection using high resolution microCT imaging combined with new, age-segmented, gait data from extant children. The age-related changes in bone structure, geometry, and architecture are linked to the development of biomechanical competence over the course of three significant transitions in a human’s life course. This chapter identifies transitions and variations in human skeletal biology, skeletal morphology, and bipedal gait as dynamic records of development. These types of ontogenetic studies provide empirical data, which function as a portal to address fundamental issues of interest to anthropologists. Examples of the types of anthropological interests include, but are not limited to, reconstructing past health and behavior; understanding the dynamics of bone growth, size, and shape; interpreting skeletal variation; and providing insight into the fossil record.

scholarly journals Metalloprotease inhibitor TIMP proteins control FGF-2 bioavailability and regulate skeletal growth

2019 ◽  
Vol 218 (9) ◽  
pp. 3134-3152 ◽  
Author(s):  
Sanjay Saw ◽  
Alison Aiken ◽  
Hui Fang ◽  
Trevor D. McKee ◽  
Sarah Bregant ◽  
...  
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Bone Development ◽  
Whole Body ◽  
Bone Lengthening ◽  
Chondrocyte Maturation ◽  
Epiphyseal Fusion ◽  
Metalloprotease Inhibitors ◽  
Metalloprotease Inhibitor ◽  
Body Stature

Regulated growth plate activity is essential for postnatal bone development and body stature, yet the systems regulating epiphyseal fusion are poorly understood. Here, we show that the tissue inhibitors of metalloprotease (TIMP) gene family is essential for normal bone growth after birth. Whole-body quadruple-knockout mice lacking all four TIMPs have growth plate closure in long bones, precipitating limb shortening, epiphyseal distortion, and widespread chondrodysplasia. We identify TIMP/FGF-2/IHH as a novel nexus underlying bone lengthening where TIMPs negatively regulate the release of FGF-2 from chondrocytes to allow IHH expression. Using a knock-in approach that combines MMP-resistant or ADAMTS-resistant aggrecans with TIMP deficiency, we uncouple growth plate activity in axial and appendicular bones. Thus, natural metalloprotease inhibitors are crucial regulators of chondrocyte maturation program, growth plate integrity, and skeletal proportionality. Furthermore, individual and combinatorial TIMP-deficient mice demonstrate the redundancy of metalloprotease inhibitor function in embryonic and postnatal development.

Taurine, Bone Growth and Bone Development

2008 ◽  
Vol 4 (2) ◽  
pp. 135-144 ◽  
Author(s):  
Sung-Jin Kim ◽  
Hyeon Lee ◽  
Ramesh Gupta
Keyword(s):  
Bone Growth ◽  
Bone Development

scholarly journals Mutations of uncertain significance in heterozygous variants as a possible cause of severe short stature: a case report

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Nami Mohammadian Khonsari ◽  
Sahar Mohammad Poor Nami ◽  
Benyamin Hakak-Zargar ◽  
Tessa Voth
Keyword(s):  
Growth Hormone ◽  
Short Stature ◽  
Hormone Receptors ◽  
Bone Growth ◽  
Synergistic Effects ◽  
Signs And Symptoms ◽  
Bone Age ◽  
Pathogenic Mutation ◽  
Paracrine Factors ◽  
Severe Short Stature

Abstract Background Linear bone growth is achieved by the division of chondrocytes at the growth plate and is regulated by endocrine and paracrine factors such as growth hormone. Mutations that negatively affect chondrogenesis can be a contributor to short stature. One such mutation can occur in the ACAN gene, causing short stature and advanced bone age. Similarly, mutations in growth hormone receptors (GHR) can lead to Laron syndrome (LS), one of the several disorders that are collectively called growth hormone insensitivity syndrome (GHI). Another example is Floating-Harbor syndrome (FHS), a rare autosomal dominant due to mutations in the SRCAP gene that can also result in short stature. Case presentation We report the case of a 6-year-old female with concomitant mutations in the three genes mentioned above. The mutations reported here were found on genetic studies and are usually benign, causing a variant of undetermined significance. However, our patient’s phenotype could only be explained by the compounded effects of pathogenic mutations of these genes. Some of the same mutations were also found in the patient’s father and her paternal grandfather. Both also presented with short stature, though not to the same degree as our patient. While these mutations are often reported to be insignificant, they gave rise to severe short stature and a specific phenotype in the patient when presented together. We think that even though the GHI spectrum is inherited through an autosomal recessive pattern, the sum of these heterozygous mutations resulted in severe short stature despite the limited GHI seen in our patient, the father, and the grandfather, through a rare ACAN and SRCAP mutation that, to our knowledge, has not been previously reported as a pathogenic mutation in the literature. Conclusion We investigated the possible synergistic effects of these variations on exacerbation or masking of the signs and symptoms of GHI with the hope of providing a better understanding of these genes and their function through our rare case.

Reconstitution of the host holobiont in germ-free born male rats acutely increases bone growth and affects marrow cellular content

2021 ◽  
Author(s):  
Piotr J Czernik ◽  
Rachel M. Golonka ◽  
Saroj Chakraborty ◽  
Beng San Yeoh ◽  
Ahmed A Abokor ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Mass ◽  
Bone Growth ◽  
Elevated Serum ◽  
Male Rats ◽  
Bone Lengthening ◽  
Mineral Density ◽  
Germ Free ◽  
Hepatic Expression ◽  
Gut Colonization

Integration of microbiota in a host begins at birth and progresses during adolescence, forming a multidirectional system of physiologic interactions. Here, we present an instantaneous effect of natural, bacterial gut colonization on the acceleration of longitudinal and radial bone growth in germ-free born, 7-week-old male rats. Changes in bone mass and structure were analyzed after 10 days following the onset of colonization through cohousing with conventional rats and revealed unprecedented acceleration of bone accrual in cortical and trabecular compartments, increased bone tissue mineral density, improved proliferation and hypertrophy of growth plate chondrocytes, bone lengthening, and preferential deposition of periosteal bone in the tibia diaphysis. In addition, the number of small in size adipocytes increased, while the number of megakaryocytes decreased, in the bone marrow of conventionalized germ-free rats indicating that not only bone mass but also bone marrow environment is under control of gut microbiota signaling. The changes in bone status paralleled with a positive shift in microbiota composition toward short chain fatty acids (SCFA)-producing microbes and a considerable increase in cecal SCFA concentrations, specifically butyrate. Further, reconstitution of the host holobiont increased hepatic expression of IGF-1 and its circulating levels. Elevated serum levels of 25-hydroxy vitamin D and alkaline phosphatase pointed toward an active process of bone formation. The acute stimulatory effect on bone growth occurred independently of body mass increase. Overall, the presented model of conventionalized germ-free rats could be used to study microbiota-based therapeutics for combatting dysbiosis-related bone disorders.

scholarly journals The Use of Mushrooms and Spirulina Algae as Supplements to Prevent Growth Inhibition in a Pre-Clinical Model for an Unbalanced Diet

Nutrients ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 4316
Author(s):  
Roni Sides ◽  
Shelley Griess-Fishheimer ◽  
Janna Zaretsky ◽  
Astar Shitrit ◽  
Rotem Kalev-Altman ◽  
...  
Keyword(s):  
Dietary Supplements ◽  
Bone Growth ◽  
Positive Impact ◽  
Bone Development ◽  
Harmful Effect ◽  
Ct Scanning ◽  
Childhood And Adolescence ◽  
Mineral Density ◽  
Clinical Model ◽  
Microbiome Composition

Today’s eating patterns are characterized by the consumption of unbalanced diets (UBDs) resulting in a variety of health consequences on the one hand, and the consumption of dietary supplements in order to achieve overall health and wellness on the other. Balanced nutrition is especially crucial during childhood and adolescence as these time periods are characterized by rapid growth and development of the skeleton. We show the harmful effect of UBD on longitudinal bone growth, trabecular and cortical bone micro-architecture and bone mineral density; which were analyzed by micro-CT scanning. Three point bending tests demonstrate the negative effect of the diet on the mechanical properties of the bone material as well. Addition of Spirulina algae or Pleurotus eryngii or Agaricus bisporus mushrooms, to the UBD, was able to improve growth and impaired properties of the bone. 16SrRNA Sequencing identified dysbiosis in the UBD rats’ microbiota, with high levels of pro-inflammatory associated bacteria and low levels of bacteria associated with fermentation processes and bone related mechanisms. These results provide insight into the connection between diet, the skeletal system and the gut microbiota, and reveal the positive impact of three chosen dietary supplements on bone development and quality presumably through the microbiome composition.

Sign in / Sign up

Export Citation Format

Share Document