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Abstract Context Collagens are the most abundant proteins in the human body. In a growth plate, collagen types II, IX, X, and XI are present. Defects in collagen genes cause heterogeneous syndromic disorders frequently associated with short stature. Less is known about oligosymptomatic collagenopathies. Objective This work aims to evaluate the frequency of collagenopathies in familial short stature (FSS) children and to describe their phenotype, including growth hormone (GH) treatment response. Methods Eighty-seven FSS children (pretreatment height ≤ –2 SD both in the patient and his or her shorter parent) treated with GH were included in the study. Next-generation sequencing was performed to search for variants in the COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, and COL11A2 genes. The results were evaluated using American College of Medical Genetics and Genomics guidelines. The GH treatment response of affected children was retrospectively evaluated. Results A likely pathogenic variant in the collagen gene was found in 10 of 87 (11.5%) children. Detailed examination described mild asymmetry with shorter limbs and mild bone dysplasia signs in 2 of 10 and 4 of 10 affected children, respectively. Their growth velocity improved from a median of 5.3 cm/year to 8.7 cm/year after 1 year of treatment. Their height improved from a median of –3.1 SD to –2.6 SD and to –2.2 SD after 1 and 3 years of therapy, respectively. The final height reached by 4 of 10 children differed by –0.67 to +1.0 SD and –0.45 to +0.5 SD compared to their pretreatment height and their affected untreated parent’s height, respectively. Conclusion Oligosymptomatic collagenopathies are a frequent cause of FSS. The short-term response to GH treatment is promising.

Obesity-associated hyperinsulinemia is hypothesized to disrupt linear growth trajectories, though the mechanisms remain unclear. This study investigates these mechanisms using a high-fat diet-induced rat model. Twelve healthy 1-week-old Sprague-Dawley rats (60-80 g) were randomized into two groups: a control group fed a standard diet and an obese group fed a high-fat diet. After 6 weeks of dietary intervention, weekly body weight and naso-anal length were recorded. At the end of the study, all rats were euthanized, and blood samples were collected for further analysis. Serum biochemical parameters, including insulin levels, were measured by ELISA. Tibiae and humeri were harvested for bone length measurement. Growth plates were isolated for histological analysis, immunohistochemistry, radioimmunoassay, PCR, and Western blotting. Higher serum insulin levels were observed in the obese group than in the control group (36.46 ± 1.69 mU/L, vs 22.96 ± 1.99 mU/L, p < 0.01). The obese group showed higher growth plate length (426.63 ± 6.28 μm, vs 331.13 ± 28.93 μm, p < 0.01), especially in proliferative and hypertrophic areas than the control group. Immunohistochemistry analysis revealed positive staining for brownish-yellow granules in these regions. Higher aromatase levels and insulin receptor (IR) expression were observed in the growth plates, primarily in the hypertrophic region. Immunohistochemical staining indicated that aromatase expression was primarily localized to the hypertrophic zone in obese rats.Moreover, the aromatase activity in the obese group was significantly higher than that in the control group (47.29 ± 0.87 U, vs 41.12 ± 1.50 U,p ＜ 0.01). The relative mRNA expression of CYP19A1 and insulin receptors (IR) in the growth plates of obese rats was significantly higher than that in the control group (0.0039 ± 0.0026-, vs 0.0001 ± 0.00025, p < 0.01 and 0.15- ± 0.07, vs 0.03 ± 0.02, p < 0.01). Western blot analysis revealed higher expression of CYP19A1 and IR in the growth plates of obese rats (1.81 ± 0.12-, vs 1.02 ± 0.04-, p < 0.01 and 2.05 ± 0.34, vs 1.04 ± 0.13-, p < 0.01). In this study, we found a significant increase in the expression of insulin receptors, indicating that insulin signaling regulates aromatase expression, thereby affecting epiphyseal growth plate development. However, the molecular mechanisms by which insulin receptors regulate aromatase expression remain unclear.

Growth plate (GP), a critical cartilaginous structure in amniotes, underpins longitudinal bone growth, yet the intricate mechanisms behind its polarized mineralization during evolution remain unclear. Herein, employing high-resolution analytical techniques, we reveal that the GP-epiphysis interface displays a sharp transition in tissue modulus, acting as a protective shell for the underlying GP, whereas the GP-metaphysis interface exhibits a gradual modulus increase, enabling efficient load redistribution to the metaphysis. This mechanical microenvironment contributes to unique microstructural and compositional transformations from GP to epiphysis and metaphysis. Notably, the GP-epiphysis interface acts as a mineralization inhibition zone while the GP-metaphysis serves as a mineralization promotion zone, orchestrated by a complex network of proteins. Proteins such as secreted phosphoprotein 1 (SPP1) and alpha-2-HS-glycoprotein (AHSG) at the GP-epiphysis interface inhibit mineralization, forming a defense line; while ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and alkaline phosphatase, biomineralization associated (ALPL), coexisting with SPP1 and AHSG, promote a sequential nucleation and assembly of calcium phosphate minerals at the GP-metaphysis. Such polarized mineralization patterns maintain the homeostasis of GPs and drive polarized bone elongation. Replicating this process in vitro, we synthesize stable amorphous calcium phosphate which shows highly controlled transformation into hydroxyapatite. This work provides a more comprehensive view of the structural integrity of human bone in development and offers strategies for controlled biomineralization. Here the authors show that the growth plate (GP)-epiphysis interface possesses a strong modulus transition and acts as a mineralization inhibition zone, while the GP-metaphysis interface has a gradual transition and stimulates bone formation. They also identify proteins at these boundaries which inhibit or promote bone mineralization.

Skeletal stem cells regulate bone growth and homeostasis by generating diverse cell types, including chondrocytes, osteoblasts and marrow stromal cells. The emerging concept postulates that there exists a distinct type of skeletal stem cell that is closely associated with the growth plate 1 – 4 , which is a type of cartilaginous tissue that has critical roles in bone elongation 5 . The resting zone maintains the growth plate by expressing parathyroid hormone-related protein (PTHrP), which interacts with Indian hedgehog (Ihh) that is released from the hypertrophic zone 6 – 10 , and provides a source of other chondrocytes 11 . However, the identity of skeletal stem cells and how they are maintained in the growth plate are unknown. Here we show, in a mouse model, that skeletal stem cells are formed among PTHrP-positive chondrocytes within the resting zone of the postnatal growth plate. PTHrP-positive chondrocytes expressed a panel of markers for skeletal stem and progenitor cells, and uniquely possessed the properties of skeletal stem cells in cultured conditions. Cell-lineage analysis revealed that PTHrP-positive chondrocytes in the resting zone continued to form columnar chondrocytes in the long term; these chondrocytes underwent hypertrophy, and became osteoblasts and marrow stromal cells beneath the growth plate. Transit-amplifying chondrocytes in the proliferating zone—which was concertedly maintained by a forward signal from undifferentiated cells (PTHrP) and a reverse signal from hypertrophic cells (Ihh)—provided instructive cues to maintain the cell fates of PTHrP-positive chondrocytes in the resting zone. Our findings unravel a type of somatic stem cell that is initially unipotent and acquires multipotency at the post-mitotic stage, underscoring the malleable nature of the skeletal cell lineage. This system provides a model in which functionally dedicated stem cells and their niches are specified postnatally, and maintained throughout tissue growth by a tight feedback regulation system. In a mouse model, PTHrP-positive chondrocytes in the resting zone of the growth plate constitute a unique stem-cell population, which is initially unipotent and makes columnar chondrocytes that later exhibit multipotency.

X-linked hypophosphatemia (XLH), the most common form of hereditary hypophosphatemic rickets, is caused by inactivating mutations of the phosphate-regulating endopeptidase gene (PHEX). XLH is mainly characterized by short stature, bone deformities and rickets, while in hypophosphatemia, normal or low vitamin D levels and low renal phosphate reabsorption are the principal biochemical aspects. The cause of growth impairment in patients with XLH is not completely understood yet, thus making the study of the growth plate (GP) alterations necessary. New treatment strategies targeting FGF23 have shown promising results in normalizing the growth velocity and improving the skeletal effects of XLH patients. However, further studies are necessary to evaluate how this treatment affects the GP as well as its long-term effects and the impact on adult height.

The activity of epiphyseal growth plates, which drives long bone elongation, depends on extensive changes in chondrocyte size and shape during differentiation. Here, we develop a pipeline called 3D Morphometric Analysis for Phenotypic significance (3D MAPs), which combines light-sheet microscopy, segmentation algorithms and 3D morphometric analysis to characterize morphogenetic cellular behaviors while maintaining the spatial context of the growth plate. Using 3D MAPs, we create a 3D image database of hundreds of thousands of chondrocytes. Analysis reveals broad repertoire of morphological changes, growth strategies and cell organizations during differentiation. Moreover, identifying a reduction in Smad 1/5/9 activity together with multiple abnormalities in cell growth, shape and organization provides an explanation for the shortening of Gdf5 KO tibias. Overall, our findings provide insight into the morphological sequence that chondrocytes undergo during differentiation and highlight the ability of 3D MAPs to uncover cellular mechanisms that may regulate this process. Inability to image large numbers of growth plate chondrocytes while retaining their spatial context during analysis has hindered the study of bone development. Here, the authors present a pipeline called 3D MAPs and use it to uncover morphogenic behaviors and growth strategies in normal bones as well as  aberrations in Gdf5 KO bones.

The widespread use of thiram has raised concerns for health and its toxic effects, but the underlying toxicity mechanism on platelets and bones is poorly defined. Here, we found a significant increase in the number of platelets in chickens with the thiram intake, due to the increased expression of thrombopoietin mRNA in the dysfunction liver. Furthermore, the decreased vascular distribution and cell death of chondrocytes in the tibial growth plates (TGPs) were observed, resulting in bone growth inhibition, which is associated with the abnormal activation of platelets leading to the extraordinary decrease of vascular endothelial growth factor A (VEGFA) and angiopoietin-1 protein were released and their corresponding receptors VEGFR2 and Tie-2 expressions were also reduced in the TGPs. Taken together, these findings revealed that thiram has an adverse effect on bones and platelets, which may have a high risk of thrombosis and osteoarthritis.

A microscopy study of the cellular basis of mammalian skeletal elongation in development and evolution reveals three phases of chondrocyte volume enlargement, including a phase of disproportionate fluid increase. Third-phase growth determines bone length There is wide variation in bone lengths in mammals, both between species and within an individual. Each of the long bones arises in the embryo as a similarly sized cartilage rudiment. Size differences develop later through differential regulation of growth of chondrocytes at the growth plate, a cartilage plate found in the metaphysis at each end of a long bone. Clifford Tabin and colleagues used diffraction phase microscopy to examine the mechanisms that control differential bone growth in rodents, and find that growth-plate chondrocytes undergo three distinct phases of volume increase. It is in the third phase — continued enlargement at low dry mass density after a phase of massive cell swelling — that variations between rapidly and slowly elongating growth plates emerge and the differences between bone lengths are established. The wide diversity of skeletal proportions in mammals is evident upon a survey of any natural history museum's collections and allows us to distinguish between species even when reduced to their calcified components. Similarly, each individual is comprised of a variety of bones of differing lengths. The largest contribution to the lengthening of a skeletal element, and to the differential elongation of elements, comes from a dramatic increase in the volume of hypertrophic chondrocytes in the growth plate as they undergo terminal differentiation 1 , 2 , 3 , 4 , 5 , 6 , 7 . However, the mechanisms of chondrocyte volume enlargement have remained a mystery 8 , 9 , 10 , 11 . Here we use quantitative phase microscopy 12 to show that mammalian chondrocytes undergo three distinct phases of volume increase, including a phase of massive cell swelling in which the cellular dry mass is significantly diluted. In light of the tight fluid regulatory mechanisms known to control volume in many cell types 13 , this is a remarkable mechanism for increasing cell size and regulating growth rate. It is, however, the duration of the final phase of volume enlargement by proportional dry mass increase at low density that varies most between rapidly and slowly elongating growth plates. Moreover, we find that this third phase is locally regulated through a mechanism dependent on insulin-like growth factor. This study provides a framework for understanding how skeletal size is regulated and for exploring how cells sense, modify and establish a volume set point.

In humans, the growth plate cartilage is completely replaced by bone in late puberty, resulting in epiphyseal fusion. However, in rats and mice, commonly used experimental model systems, the growth plate does not fuse completely even after sexual maturation, making it difficult to elucidate mechanisms involved in epiphyseal fusion. In this study, we investigated age-related changes in the mouse growth plate to better understand the process of epiphyseal fusion. We used scanning electron microscopy and energy-dispersive X-ray spectroscopy (SEM/EDS) to examine the distributions and concentrations of minerals in the growth plate. In SEM images, the hypertrophic zone was observed as a bright area and other zones as dark areas at 10 weeks of age (W10). The bright area was further expanded at W55 than at W10. EDS analysis showed that P and Ca concentrations were high in this area, while C and O concentrations were low, indicating that the growth plate had calcified during aging. Alcian blue histochemistry revealed that the glycosaminoglycans of aggrecan were distributed in the growth plate at both W10 and W55. Immunohistochemistry showed that aggrecan and type II collagen were expressed throughout the growth plate at W10, but sparsely at W55. Type I collagen was expressed weak at both W10 and W55. Type X collagen and MMP-13 expression were observed in the hypertrophic zone at W10 but not at W55. This study demonstrated that although the mouse growth plate calcifies with age, it remains calcified cartilage for an extended period without being replaced by bone.

Vertebrates do not look like jellyfish because the bones of their skeletons are levers that allow movement and protect vital organs. Bones come in an enormous variety of shapes and sizes to accomplish these goals, but, with few exceptions, use one process--endochondral bone formation--to generate the skeleton. The past few years have seen an enormous increase in understanding of the signalling pathways and the transcription factors that control endochondral bone development.