Filamin B regulates chondrocyte proliferation and differentiation through Cdk1 signaling.

Abstract

Humans who harbor loss of function mutations in the actin-associated filamin B (FLNB) gene develop spondylocarpotarsal syndrome (SCT), a disorder characterized by dwarfism (delayed bone formation) and premature fusion of the vertebral, carpal and tarsal bones (premature differentiation). To better understand the cellular and molecular mechanisms governing these seemingly divergent processes, we generated and characterized FlnB knockdown ATDC5 cell lines. We found that FlnB knockdown led to reduced proliferation and enhanced differentiation in chondrocytes. Within the shortened growth plate of postnatal FlnB(-/-) mice long bone, we observed a similarly progressive decline in the number of rapidly proliferating chondrocytes and premature differentiation characterized by an enlarged prehypertrophic zone, a widened Col2a1(+)/Col10a1(+) overlapping region, but relatively reduced hypertrophic zone length. The reduced chondrocyte proliferation and premature differentiation were, in part, attributable to enhanced G2/M phase progression, where fewer FlnB deficient ATDC5 chondrocytes resided in the G2/M phase of the cell cycle. FlnB loss reduced Cdk1 phosphorylation (an inhibitor of G2/M phase progression) and Cdk1 inhibition in chondrocytes mimicked the null FlnB, premature differentiation phenotype, through a β1-integrin receptor- Pi3k/Akt (a key regulator of chondrocyte differentiation) mediated pathway. In this context, the early prehypertrophic differentiation provides an explanation for the premature differentiation seen in this disorder, whereas the progressive decline in proliferating chondrocytes would ultimately lead to reduced chondrocyte production and shortened bone length. These findings begin to define a role for filamin proteins in directing both cell proliferation and differentiation through indirect regulation of cell cycle associated proteins.

• Authors: Jianjun Hu, Jie Lu, Gewei Lian, Jingping Zhang, Jonathan L Hecht, Volney L Sheen
• Journal: PloS one (PLoS One) Vol. 9 Issue 2 Pg. e89352 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24551245 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cyclin B
• Filamins
• Integrin beta1
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• CDC2 Protein Kinase

Topics

• Animals
• Animals, Newborn
• Bone and Bones (metabolism, pathology)
• CDC2 Protein Kinase (antagonists & inhibitors, metabolism)
• Cell Cycle
• Cell Differentiation
• Cell Proliferation
• Chondrocytes (cytology, enzymology)
• Cyclin B (metabolism)
• Down-Regulation
• Filamins (deficiency, metabolism)
• Gene Knockdown Techniques
• Humans
• Hypertrophy
• Integrin beta1 (metabolism)
• Mice
• Phenotype
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction