ReferenceID 3471
Inactivation of Nell-1 in Chondrocytes Significantly Impedes Appendicular Skeletogenesis
J Bone Miner Res
NELL-1, an osteoinductive protein, has been shown to regulate skeletal ossification. Interestingly, an interstitial 11p14.1-p15.3 deletion involving the Nell-1 gene was recently reported in a patient with short stature a
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- Reference Id
- 3471
- Evidence Id
- 20061
- Core Evidence Id
- 20061
- Source Reference Id
- 247
- Herb2 Reference Id
- HBREF000461
- Subject Paper Key
- HBIN022330_30352124
- Pubmed Id
- 30352124
- Doi
- 10.1002/jbmr.3615
- Paper Title
- Inactivation of Nell-1 in Chondrocytes Significantly Impedes Appendicular Skeletogenesis
- Paper Abstract
- NELL-1, an osteoinductive protein, has been shown to regulate skeletal ossification. Interestingly, an interstitial 11p14.1-p15.3 deletion involving the Nell-1 gene was recently reported in a patient with short stature and delayed fontanelle closure. Here we sought to define the role of Nell-1 in endochondral ossification by investigating Nell-1-specific inactivation in Col2α1-expressing cell lineages. Nell-1flox/flox ; Col2α1-Cre+ (Nell-1Col2α1 KO) mice were generated for comprehensive analysis. Nell-1Col2α1 KO mice were born alive but displayed subtle femoral length shortening. At 1 and 3 months postpartum, Nell-1 inactivation resulted in dwarfism and premature osteoporotic phenotypes. Specifically, Nell-1Col2α1 KO femurs and tibias exhibited significantly reduced length, bone mineral density (BMD), bone volume per tissue volume (BV/TV), trabecular number/thickness, cortical volume/thickness/density, and increased trabecular separation. The decreased bone formation rate revealed by dynamic histomorphometry was associated with altered numbers and/or function of osteoblasts and osteoclasts. Furthermore, longitudinal observations by in vivo micro-CT showed delayed and reduced mineralization at secondary ossification centers in mutants. Histologically, reduced staining intensities of Safranin O, Col-2, Col-10, and fewer BrdU-positive chondrocytes were observed in thinner Nell-1Col2α1 KO epiphyseal plates along with altered distribution and weaker expression level of Ihh, Patched-1, PTHrP, and PTHrP receptor. Primary Nell-1Col2α1 KO chondrocytes also exhibited decreased proliferation and differentiation, and its downregulated expression of the Ihh-PTHrP signaling molecules can be partially rescued by exogenous Nell-1 protein. Moreover, intranuclear Gli-1 protein and gene expression of the Gli-1 downstream target genes, Hip-1 and N-Myc, were also significantly decreased with Nell-1 inactivation. Notably, the rescue effects were diminished/reduced with application of Ihh signaling inhibitors, cyclopamine or GANT61. Taken together, these findings suggest that Nell-1 is a pivotal modulator of epiphyseal homeostasis and endochondral ossification. The cumulative chondrocyte-specific Nell-1 inactivation significantly impedes appendicular skeletogenesis resulting in dwarfism and premature osteoporosis through inhibiting Ihh signaling and predominantly altering the Ihh-PTHrP feedback loop. 2018 American Society for Bone and Mineral Research.
- Journal
- J Bone Miner Res
- Publish Year
- 2019
- Experiment Subject
- nell-1col2alpha1ko mice
- Experiment Type
- Animal Experiment
- Phenotype Related
- Osteoporosis
- Paper Title Cn
- Paper Title En
- Inactivation of Nell-1 in Chondrocytes Significantly Impedes Appendicular Skeletogenesis
- Bilingual Status
- semi_complete