Premature Ossification and Reduced Osteoclast Formation in Ninein-Deficient Mice

Core Concepts

Absence of the centrosomal protein ninein leads to premature ossification and reduced osteoclast formation, resulting in structural changes in developing long bones.

Abstract

The study investigates the role of the centrosomal protein ninein in skeletal development using a ninein knockout mouse model. Key findings:

Ninein-deficient mice exhibit advanced endochondral and intramembranous ossification during embryonic development, leading to premature closure of the interfrontal suture.

The premature ossification is accompanied by a reduction in the number of multinucleated osteoclasts, the bone-resorbing cells, at early stages of bone development.

In the absence of ninein, osteoclast precursors display defects in cell fusion, resulting in fewer mature, multinucleated osteoclasts. This is attributed to abnormalities in centrosome cohesion and microtubule organization.

The reduced osteoclast formation leads to structural changes in the developing trabecular bone of the tibia, with increased mineralization in the central region compared to controls.

The authors propose that the centrosomal functions of ninein, particularly in regulating microtubule organization and cell fusion, are crucial for the balance between bone-forming osteoblasts and bone-resorbing osteoclasts during skeletal development.

Stats

"Litter size comparisons following crossings among control or ninein-deleted animals at birth showed a reduction in the number of live pups by nearly 50% in the absence of ninein."
"Analysis of mineralization in the digits revealed an additional ossification center in the intermediate phalanges of digits 2-4 in ninein-deleted embryos compared to controls at E18.5."
"Quantification of TRAP-positive osteoclasts in the mandible area of E14.5 embryos showed a significant reduction in the percentage of multinucleated osteoclasts in ninein-deleted embryos compared to controls."
"Bone resorption assays demonstrated that the resorption area of osteoclasts lacking ninein was smaller than that of controls."

Quotes

"We propose that centrosomal ninein is important for osteoclast fusion, to enable a functional balance between bone-forming osteoblasts and bone-resorbing osteoclasts during skeletal development."
"Altogether, the ninein-dependent defects at the cellular level are subtle, since cell proliferation and osteoclast fusion still take place, albeit less efficiently."

Key Insights Distilled From

Loss of ninein interferes with osteoclast formation and causes premature ossification

by Gilbert,T., ... at www.biorxiv.org 11-06-2023

https://www.biorxiv.org/content/10.1101/2023.11.03.565572v1

Deeper Inquiries

How might the premature ossification and reduced osteoclast formation observed in ninein-deficient mice contribute to the skeletal abnormalities seen in human patients with Seckel syndrome and spondyloepimetaphyseal dysplasia?

The premature ossification and reduced osteoclast formation observed in ninein-deficient mice can directly impact skeletal development and homeostasis, leading to skeletal abnormalities seen in human patients with Seckel syndrome and spondyloepimetaphyseal dysplasia. In the context of Seckel syndrome, which is characterized by microcephaly and dwarfism, the reduced pool of multinucleated osteoclasts due to fusion defects in the absence of ninein can disrupt the balance between bone formation and resorption. This imbalance can result in abnormal bone growth and mineralization, contributing to the skeletal dysplasia observed in Seckel syndrome patients. Additionally, the premature closure of skull sutures, a common feature in Seckel syndrome, can be attributed to the early intramembranous ossification seen in ninein-deficient mice, leading to craniosynostosis in human patients with Seckel syndrome.
In the case of spondyloepimetaphyseal dysplasia, which is characterized by short stature, joint laxity, and skeletal abnormalities, the reduced osteoclastogenesis and impaired bone resorption in ninein-deficient mice can lead to altered bone growth and mineralization patterns. The fusion defects in osteoclast precursors can result in inefficient bone remodeling, affecting the structural integrity and growth of bones. The dysregulation of osteoclast function due to ninein deficiency may contribute to the skeletal abnormalities observed in patients with spondyloepimetaphyseal dysplasia, such as joint laxity and abnormal bone morphology.

How might the premature ossification and reduced osteoclast formation observed in ninein-deficient mice contribute to the skeletal abnormalities seen in human patients with Seckel syndrome and spondyloepimetaphyseal dysplasia?

The premature ossification and reduced osteoclast formation observed in ninein-deficient mice can directly impact skeletal development and homeostasis, leading to skeletal abnormalities seen in human patients with Seckel syndrome and spondyloepimetaphyseal dysplasia. In the context of Seckel syndrome, which is characterized by microcephaly and dwarfism, the reduced pool of multinucleated osteoclasts due to fusion defects in the absence of ninein can disrupt the balance between bone formation and resorption. This imbalance can result in abnormal bone growth and mineralization, contributing to the skeletal dysplasia observed in Seckel syndrome patients. Additionally, the premature closure of skull sutures, a common feature in Seckel syndrome, can be attributed to the early intramembranous ossification seen in ninein-deficient mice, leading to craniosynostosis in human patients with Seckel syndrome.
In the case of spondyloepimetaphyseal dysplasia, which is characterized by short stature, joint laxity, and skeletal abnormalities, the reduced osteoclastogenesis and impaired bone resorption in ninein-deficient mice can lead to altered bone growth and mineralization patterns. The fusion defects in osteoclast precursors can result in inefficient bone remodeling, affecting the structural integrity and growth of bones. The dysregulation of osteoclast function due to ninein deficiency may contribute to the skeletal abnormalities observed in patients with spondyloepimetaphyseal dysplasia, such as joint laxity and abnormal bone morphology.

How might the premature ossification and reduced osteoclast formation observed in ninein-deficient mice contribute to the skeletal abnormalities seen in human patients with Seckel syndrome and spondyloepimetaphyseal dysplasia?

The premature ossification and reduced osteoclast formation observed in ninein-deficient mice can directly impact skeletal development and homeostasis, leading to skeletal abnormalities seen in human patients with Seckel syndrome and spondyloepimetaphyseal dysplasia. In the context of Seckel syndrome, which is characterized by microcephaly and dwarfism, the reduced pool of multinucleated osteoclasts due to fusion defects in the absence of ninein can disrupt the balance between bone formation and resorption. This imbalance can result in abnormal bone growth and mineralization, contributing to the skeletal dysplasia observed in Seckel syndrome patients. Additionally, the premature closure of skull sutures, a common feature in Seckel syndrome, can be attributed to the early intramembranous ossification seen in ninein-deficient mice, leading to craniosynostosis in human patients with Seckel syndrome.
In the case of spondyloepimetaphyseal dysplasia, which is characterized by short stature, joint laxity, and skeletal abnormalities, the reduced osteoclastogenesis and impaired bone resorption in ninein-deficient mice can lead to altered bone growth and mineralization patterns. The fusion defects in osteoclast precursors can result in inefficient bone remodeling, affecting the structural integrity and growth of bones. The dysregulation of osteoclast function due to ninein deficiency may contribute to the skeletal abnormalities observed in patients with spondyloepimetaphyseal dysplasia, such as joint laxity and abnormal bone morphology.