scholarly journals Role of iRhoms 1 and 2 in Endochondral Ossification

2020 ◽  
Vol 21 (22) ◽  
pp. 8732
Author(s):  
Renpeng Fang ◽  
Coline Haxaire ◽  
Miguel Otero ◽  
Samantha Lessard ◽  
Gisela Weskamp ◽  
...  
Keyword(s):  
Growth Plate ◽  
Endochondral Ossification ◽  
Bone Growth ◽  
Egf Receptor ◽  
Hypertrophic Chondrocytes ◽  
Egfr Mutations ◽  
Appendicular Skeleton ◽  
Growth Plates ◽  
Egfr Ligands

Growth of the axial and appendicular skeleton depends on endochondral ossification, which is controlled by tightly regulated cell–cell interactions in the developing growth plates. Previous studies have uncovered an important role of a disintegrin and metalloprotease 17 (ADAM17) in the normal development of the mineralized zone of hypertrophic chondrocytes during endochondral ossification. ADAM17 regulates EGF-receptor signaling by cleaving EGFR-ligands such as TGFα from their membrane-anchored precursor. The activity of ADAM17 is controlled by two regulatory binding partners, the inactive Rhomboids 1 and 2 (iRhom1, 2), raising questions about their role in endochondral ossification. To address this question, we generated mice lacking iRhom2 (iR2−/−) with floxed alleles of iRhom1 that were specifically deleted in chondrocytes by Col2a1-Cre (iR1∆Ch). The resulting iR2−/−iR1∆Ch mice had retarded bone growth compared to iR2−/− mice, caused by a significantly expanded zone of hypertrophic mineralizing chondrocytes in the growth plate. Primary iR2−/−iR1∆Ch chondrocytes had strongly reduced shedding of TGFα and other ADAM17-dependent EGFR-ligands. The enlarged zone of mineralized hypertrophic chondrocytes in iR2−/−iR1∆Ch mice closely resembled the abnormal growth plate in A17∆Ch mice and was similar to growth plates in Tgfα−/− mice or mice with EGFR mutations. These data support a model in which iRhom1 and 2 regulate bone growth by controlling the ADAM17/TGFα/EGFR signaling axis during endochondral ossification.

scholarly journals ADAM17 Controls Endochondral Ossification by Regulating Terminal Differentiation of Chondrocytes

2013 ◽  
Vol 33 (16) ◽  
pp. 3077-3090 ◽  
Author(s):  
Katherine C. Hall ◽  
Daniel Hill ◽  
Miguel Otero ◽  
Darren A. Plumb ◽  
Dara Froemel ◽  
...  
Keyword(s):  
Growth Factor ◽  
Growth Plate ◽  
Endochondral Ossification ◽  
Terminal Differentiation ◽  
Cell Interactions ◽  
Hypertrophic Chondrocytes ◽  
Main Role ◽  
Egfr Signaling ◽  
Cell Cell

Endochondral ossification is a highly regulated process that relies on properly orchestrated cell-cell interactions in the developing growth plate. This study is focused on understanding the role of a crucial regulator of cell-cell interactions, the membrane-anchored metalloproteinase ADAM17, in endochondral ossification. ADAM17 releases growth factors, cytokines, and other membrane proteins from cells and is essential for epidermal growth factor receptor (EGFR) signaling and for processing tumor necrosis factor alpha. Here, we report that mice lacking ADAM17 in chondrocytes (A17ΔCh) have a significantly expanded zone of hypertrophic chondrocytes in the growth plate and retarded growth of long bones. This abnormality is caused by an accumulation of the most terminally differentiated type of chondrocytes that produces a calcified matrix. Inactivation of ADAM17 in osteoclasts or endothelial cells does not affect the zone of hypertrophic chondrocytes, suggesting that the main role of ADAM17 in the growth plate is in chondrocytes. This notion is further supported byin vitroexperiments showing enhanced hypertrophic differentiation of primary chondrocytes lackingAdam17. The enlarged zone of hypertrophic chondrocytes inA17ΔChmice resembles that described in mice with mutant EGFR signaling or lack of its ligand transforming growth factor α (TGFα), suggesting that ADAM17 regulates terminal differentiation of chondrocytes during endochondral ossification by activating the TGFα/EGFR signaling axis.

scholarly journals Glycogen synthase kinase 3 alpha/beta deletion induces precocious growth plate remodeling and cell loss in mice

2020 ◽  
Author(s):  
Supinder Kour Bali ◽  
Dawn Bryce ◽  
Carina Prein ◽  
James R. Woodgett ◽  
Frank Beier
Keyword(s):  
Articular Cartilage ◽  
Growth Plate ◽  
Bone Growth ◽  
Glycogen Synthase ◽  
Final Height ◽  
Glycogen Synthase Kinase ◽  
Metabolic Phenotype ◽  
Endochondral Bone ◽  
Growth Plates

ABSTRACTGlycogen synthase kinase (GSK) 3 acts to negatively regulate multiple signaling pathways, including canonical Wnt signaling. The two mammalian GSK3 proteins (alpha and beta) are at least partially redundant. While Gsk3a KO mice are viable and display a metabolic phenotype, abnormal neuronal development and accelerated aging, Gsk3b KO animals die late in embryogenesis or at birth. Selective Gsk3b KO in bone delayed development of some bones, whereas cartilage-specific Gsk3b KO mice are normal except for elevated levels of GSK3alpha protein. However, the collective role of these two GSK3 proteins in cartilage was not evaluated. To address this, we generated tamoxifen-inducible, cartilage-specific Gsk3a/Gsk3b KO in juvenile mice and investigated their skeletal phenotypes. We found that cartilage-specific Gsk3a/Gsk3b deletion in young, skeletally immature mice causes precocious growth plate remodeling, culminating in shorter long bones and hence, growth retardation. These mice exhibit inefficient breathing patterns at later stages and fail to survive. The disrupted growth plates in KO mice showed progressive loss of cellular and proteoglycan components and Sox9 positive cells, with increased staining for osteocalcin and type II collagen. In addition, an increase in osteoclast recruitment and cell apoptosis was observed in growth plates. Surprisingly, changes in articular cartilage of Gsk3a/Gsk3b KO mice were mild compared to growth plates, signifying differential regulation of articular cartilage vs growth plate tissues. Taken together, these findings emphasize a crucial role of two GSK3 proteins in skeletal development, in particular in the maintenance and function of growth plates.SignificanceGrowth plate cartilage dynamics determine the rate of endochondral bone growth and thus, our final height. These processes are disturbed in many genetic and acquired diseases, but the intracellular mechanisms responsible for normal growth plate function, as well as the cessation of growth plate activity in puberty, are poorly understood. Here, we demonstrate that specific removal of both GSK3 genes (Gsk3a and Gsk3b) in postnatal cartilage of mice leads to a severe reduction of endochondral bone growth, premature remodelling of the growth plate, and early death. In contrast, articular cartilage is only mildly affected by deletion of both genes. These studies identify GSK3 signaling as a key regulator of growth plate dynamics and endochondral bone growth.

scholarly journals The role of estrogen receptor-α and its activation function-1 for growth plate closure in female mice

2012 ◽  
Vol 302 (11) ◽  
pp. E1381-E1389 ◽  
Author(s):  
A. E. Börjesson ◽  
S. H. Windahl ◽  
E. Karimian ◽  
E. E. Eriksson ◽  
M. K. Lagerquist ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Growth Plate ◽  
Bone Growth ◽  
High Dose ◽  
Plate Height ◽  
Chondrocyte Proliferation ◽  
Growth Plates ◽  
Longitudinal Bone Growth ◽  
Female Mice

High estradiol levels in late puberty induce growth plate closure and thereby cessation of growth in humans. In mice, the growth plates do not fuse after sexual maturation, but old mice display reduced longitudinal bone growth and high-dose estradiol treatment induces growth plate closure. Estrogen receptor (ER)-α stimulates gene transcription via two activation functions (AFs), AF-1 and AF-2. To evaluate the role of ERα and its AF-1 for age-dependent reduction in longitudinal bone growth and growth plate closure, female mice with inactivation of ERα (ERα−/−) or ERαAF-1 (ERαAF-10) were evaluated. Old (16- to 19-mo-old) female ERα−/− mice showed continued substantial longitudinal bone growth, resulting in longer bones (tibia: +8.3%, P < 0.01) associated with increased growth plate height (+18%, P < 0.05) compared with wild-type (WT) mice. In contrast, the longitudinal bone growth ceased in old ERαAF-10 mice (tibia: −4.9%, P < 0.01). Importantly, the proximal tibial growth plates were closed in all old ERαAF-10 mice while they were open in all WT mice. Growth plate closure was associated with a significantly altered balance between chondrocyte proliferation and apoptosis in the growth plate. In conclusion, old female ERα−/− mice display a prolonged and enhanced longitudinal bone growth associated with increased growth plate height, resembling the growth phenotype of patients with inactivating mutations in ERα or aromatase. In contrast, ERαAF-1 deletion results in a hyperactive ERα, altering the chondrocyte proliferation/apoptosis balance, leading to growth plate closure. This suggests that growth plate closure is induced by functions of ERα that do not require AF-1 and that ERαAF-1 opposes growth plate closure.

scholarly journals Catch-Up Growth after Hypothyroidism Is Caused by Delayed Growth Plate Senescence

Endocrinology ◽  
2008 ◽  
Vol 149 (4) ◽  
pp. 1820-1828 ◽  
Author(s):  
Rose Marino ◽  
Anita Hegde ◽  
Kevin M. Barnes ◽  
Lenneke Schrier ◽  
Joyce A. Emons ◽  
...  
Keyword(s):  
Growth Rate ◽  
Growth Inhibition ◽  
Growth Plate ◽  
Bone Growth ◽  
Structural Characteristics ◽  
Linear Growth Rate ◽  
Growth Plate Chondrocytes ◽  
Growth Plates ◽  
Catch Up ◽  
Growth Inhibiting

Catch-up growth is defined as a linear growth rate greater than expected for age after a period of growth inhibition. We hypothesized that catch-up growth occurs because growth-inhibiting conditions conserve the limited proliferative capacity of growth plate chondrocytes, thus slowing the normal process of growth plate senescence. When the growth-inhibiting condition resolves, the growth plates are less senescent and therefore grow more rapidly than normal for age. To test this hypothesis, we administered propylthiouracil to newborn rats for 8 wk to induce hypothyroidism and then stopped the propylthiouracil to allow catch-up growth. In untreated controls, the growth plates underwent progressive, senescent changes in multiple functional and structural characteristics. We also identified genes that showed large changes in mRNA expression in growth plate and used these changes as molecular markers of senescence. In treated animals, after stopping propylthiouracil, these functional, structural, and molecular senescent changes were delayed, compared with controls. This delayed senescence included a delayed decline in longitudinal growth rate, resulting in catch-up growth. The findings demonstrate that growth inhibition due to hypothyroidism slows the developmental program of growth plate senescence, including the normal decline in the rate of longitudinal bone growth, thus accounting for catch-up growth.

scholarly journals Inner histopathologic changes and disproportionate zone volumes in foetal growth plates following gestational hypoglycaemia in rats

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Vivi F. H. Jensen ◽  
Anne-Marie Mølck ◽  
Ingrid B. Bøgh ◽  
Jette Nowak ◽  
Birgitte M. Viuff ◽  
...  
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Skeletal Development ◽  
Long Bone ◽  
Structural Protein ◽  
Pregnant Rats ◽  
Growth Plates ◽  
Chondrocyte Maturation ◽  
Foetal Growth ◽  
Histopathologic Changes

AbstractMaternal hypoglycaemia throughout gestation until gestation day (GD)20 delays foetal growth and skeletal development. While partially prevented by return to normoglycaemia after completed organogenesis (GD17), underlying mechanisms are not fully understood. Here, we investigated the pathogenesis of these changes and significance of maternal hypoglycaemia extending beyond organogenesis in non-diabetic rats. Pregnant rats received insulin-infusion until GD20 or GD17, with sacrifice on GD20. Hypoglycaemia throughout gestation increased maternal corticosterone levels, which correlated with foetal levels. Growth plates displayed central histopathologic changes comprising disrupted cellular organisation, hypertrophic chondrocytes, and decreased cellular density; expression of pro-angiogenic factors, HIF-1α and VEGF-A increased in surrounding areas. Disproportionately decreased growth plate zone volumes and lower expression of the structural protein MATN-3 were seen, while bone ossification parameters were normal. Ending maternal/foetal hypoglycaemia on GD17 reduced incidence and severity of histopathologic changes and with normal growth plate volume. Compromised foetal skeletal development following maternal hypoglycaemia throughout gestation is hypothesised to result from corticosterone-induced hypoxia in growth plates, where hypoxia disrupts chondrocyte maturation and growth plate structure and volume, decreasing long bone growth. Maternal/foetal hypoglycaemia lasting only until GD17 attenuated these changes, suggesting a pivotal role of glucose in growth plate development.

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.

Hyaluronan contributes to the enlargement of hypertrophic lacunae in the growth plate

1996 ◽  
Vol 109 (2) ◽  
pp. 327-334 ◽  
Author(s):  
P. Pavasant ◽  
T. Shizari ◽  
C.B. Underhill
Keyword(s):  
Hydrostatic Pressure ◽  
Organ Culture ◽  
Growth Plate ◽  
Histochemical Staining ◽  
Culture Conditions ◽  
Hypertrophic Chondrocytes ◽  
Growth Plates ◽  
Normal Culture ◽  
Autoradiographic Analysis

Histochemical staining of the epiphysial growth plate revealed that free hyaluronan (i.e. available to the staining probe) was restricted to the zone of hypertrophy, where it was located in the pericellular space between the chondrocytes and the edge of the lacunae. Furthermore, the amount of hyaluronan staining was directly proportional to the size of the lacunae. Autoradiographic analysis of growth plates cultured with isotopically labeled glucosamine indicated that at least a portion of this hyaluronan was newly synthesized by the hypertrophic chondrocytes. Since hyaluronan can adsorb large amounts of water, it is possible that it exerted a hydrostatic pressure on the surrounding territorial matrix and thereby caused the expansion of hypertrophic lacunae. To assess this possibility, segments of the growth plate were placed in organ culture under different conditions. Under normal culture conditions, a band of hyaluronan staining migrated across the segments coinciding with the enlargement of lacunae in these regions, and the segments, as a whole, increased in size. In contrast, when the segments were cultured in the presence of hyaluronidase, which degraded the pericellular hyaluronan, the lacunae did not undergo enlargement and the overall size of the segments did not increase. These results suggest that the production of hyaluronan contributes to the enlargement of hypertrophic lacunae which is important for determining both the body's stature and proportions.

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