Physiological regulation of bone length and skeletal proportion in mammals

Zhou, Elaine; Lui, Julian C.

doi:10.1113/ep089086

Cited by 8 publications

(7 citation statements)

References 52 publications

(65 reference statements)

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“…Histological analysis of the proximal tibial growth plate showed an overall increase in the growth plate height of the male KO mice ( Figure 4, A and B ), which prompted us to quantitatively analyze the different zones in the growth plate. The 3 zones of the growth plate — resting, proliferative, and hypertrophic — correspond to the stem-like progenitors, the actively dividing transit-amplifying cells, and the terminally differentiated collagen X–producing chondrocytes, respectively ( 16 ).…”

Section: Resultsmentioning

confidence: 99%

“…Again, we assessed a possible involvement of IGF-2 in the altered body growth but neither serum IGF-2 levels nor mRNA levels of Igf2 or H19 (measured in liver and cultured growth plate chondrocytes) showed any significant difference between male KO mice and male wild-type littermates at 2 weeks of age (Supplemental Histological analysis of the proximal tibial growth plate showed an overall increase in the growth plate height of the male KO mice (Figure 4A, B), which prompted us to quantitatively analyze the different zones in the growth plate. The three zones of the growth plate, resting, proliferative, and hypertrophic, correspond to the stem-like progenitors, the actively-dividing transit-amplifying cells, and the terminally-differentiated collagen X-producing chondrocytes, respectively (15).…”

Section: Expanded Resting Zone Of the Growth Plate In Spin4 Ko Micementioning

confidence: 99%

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Loss-of-function variant in SPIN4 causes an X-linked overgrowth syndrome

Lui¹,

Wagner²,

Zhou³

et al. 2023

JCI Insight

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Overgrowth syndromes can be caused by pathogenic genetic variants in epigenetic writers, such as DNA and histone methyltransferases. However, no overgrowth disorder has previously been ascribed to variants in a gene that acts primarily as an epigenetic reader. Here, we studied a male individual with generalized overgrowth of prenatal onset. Exome sequencing identified a hemizygous frameshift variant in Spindlin 4 (SPIN4), with X-linked inheritance. We found evidence that SPIN4 binds specific histone modifications, promotes canonical WNT signaling, and inhibits cell proliferation in vitro and that the identified frameshift variant had lost all of these functions. Ablation of Spin4 in mice recapitulated the human phenotype with generalized overgrowth, including increased longitudinal bone growth. Growth plate analysis revealed increased cell proliferation in the proliferative zone and an increased number of progenitor chondrocytes in the resting zone. We also found evidence of decreased canonical Wnt signaling in growth plate chondrocytes, providing a potential explanation for the increased number of resting zone chondrocytes.Taken together, our findings provide strong evidence that SPIN4 is an epigenetic reader that negatively regulates mammalian body growth, and that loss of SPIN4 causes an overgrowth syndrome in humans, expanding our knowledge of the epigenetic regulation of human growth. 4like domains, with SPIN1, an epigenetic reader which recognizes histone H3 trimethylated at lysine-4 (8, 9) and H3 asymmetrically dimethylated at arginine-8 (10). SPIN1 has also been shown to stimulate Wnt signaling and promote cell proliferation and cancer progression (11,12).We evaluated a male individual with generalized overgrowth of prenatal onset, which, at the time of clinical presentation, included extreme tall stature, enlarged liver and spleen, and macrocephaly but no developmental delay. Exome sequencing identified a protein-truncating frameshift variant in SPIN4. In mice, ablation of Spin4 resulted in overgrowth of multiple organs and overall body size, recapitulating the human phenotype. We found that wild-type SPIN4 was able to bind specifically modified histone H3, promote canonical WNT signaling, and inhibit cell proliferation in vitro, but that the variant of SPIN4, which lacks two of the three Tudor-like domains, had lost all of these functions. The findings indicate that SPIN4 normally serves as an epigenetic reader which negatively regulates body size in mice and humans, and, therefore, loss of function of Spin4/SPIN4 increases somatic growth. Results Proband and the familyThe proband was a 13-year-old boy who was referred for evaluation of an overgrowth syndrome. He was born large for gestational age, with a birth weight of 5.85 kg (+4.3 SDS) and a length of 62 cm (+4.8 SDS). The mother had no history of gestational diabetes. He has been growing remarkably with height tracking between +4.5 and +5 SDS, although his mid-parental height was +1.2 SDS (Figure 1A). His bone age was advanced by one year; 13 years...

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Section: Resultsmentioning

confidence: 99%

Section: Expanded Resting Zone Of the Growth Plate In Spin4 Ko Micementioning

confidence: 99%

Loss-of-function variant in SPIN4 causes an X-linked overgrowth syndrome

Lui¹,

Wagner²,

Zhou³

et al. 2023

JCI Insight

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“…It has a more regular shape and it is smaller compared to the calcaneus. For these reasons, it seems reasonable to determine that four additional PCs are needed to explain a bigger and hence more complex bone [ 35 ] for the calcaneus.…”

Section: Discussionmentioning

confidence: 99%

Parametrization of the Calcaneus and Medial Cuneiform to Aid Potential Advancements in Flatfoot Surgery

Cai,

Pascoletti,

Zioupos

et al. 2024

Life

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Introduction: Flatfoot is a condition commonly seen in children; however, there is general disagreement over its incidence, characterization and correction. Painful flatfoot accompanied with musculoskeletal and soft tissue problems requires surgery to avoid arthritis in adulthood, the most common surgical approach being two osteotomies to the calcaneus and medial cuneiform bones of the foot. Objectives: This study focuses on the parametrization of these two bones to understand their bone morphology differences in a population sample among 23 normal subjects. Population differences could help in understanding whether bone shape may be an important factor in aiding surgical planning and outcomes. Methods: A total of 45 sets of CT scans of these subjects were used to generate surface meshes of the two bones and converted to be iso-topological meshes, simplifying the application of Generalized Procrustes Analysis and Principal Component Analysis, allowing the main sources of variation between the subjects to be quantified. Results: For the calcaneus, 16 Principal Components (PCs) and, for the medial cuneiform, 12 PCs were sufficient to describe 90% of the dataset variability. The quantitative and qualitative analyses confirm that for the calcaneus PC1 describes the Achilles attachment location and PC2 largely describes the anterior part of the bone. For the medial cuneiform, PC1 describes the medial part of the bone, while PC2 mainly describes the superior part. Conclusion: Most importantly, the PCs did not seem to describe the osteotomy sites for both bones, suggesting low population variability at the bone cutting points. Further studies are needed to evaluate how shape variability impacts surgical outcomes. Future implications could include better surgical planning and may pave the way for complex robotic surgeries to become a reality.

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“…In the article by Zhou & Lui (2021), ‘Physiological regulation of bone length and skeletal proportion in mammals’. Exp Physiol .…”

Section: Figurementioning

confidence: 99%