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Novel role for cyclophilin A in regulation of chondrogenic commitment and endochondral ossification

Significance Statement

Chondrogenesis is an essential process in vertebrates. It leads to the formation of cartilage growth plates, thereby driving bodily growth while providing structural templates and induction signals for the formation of long bones through endochondral ossification. On the other hand, defects in chondrogenesis causes various chondrodysostoses and chondrodysplasias, with such skeletal malformations accounting for a significant proportion of human birth defects that often result in embryonic and perinatal lethality. The molecular mechanisms that drive chondrocyte differentiation and impact underlying cartilage diseases remain to be elucidated. Either knock-down of cyclophilin A (CypA) or pharmacological inhibition of cyclophilin A or NF-κB reduces or delays BMP-2 induced chondrogenic differentiation. cyclophilin A-deficient mice display chondrodysplasias and defective endochondral bone formation. Clearly cyclophilin A is required for chondrogenic differentiation and endochondral ossification. Studies of molecular details are important to better understand BMP-2-induced chondrogenesis signaling during vertebrate development and will help to develop better strategies for tissue repair and treatment of cartilage related diseases.

 

Journal Reference

Mol Cell Biol. 2015;35(12):2119-30.

Guo M1, Shen J2, Kwak JH2, Choi B3, Lee M3, Hu S4, Zhang X2, Ting K2, Soo CB5, Chiu RH6.

Show Affiliations
  1. Dental and Craniofacial Research Institute and Division of Oral Biology, School of Dentistry, University of California, Los Angeles, Los Angeles, California, USA Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
  2. Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, California, USA.
  3. Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, California, USA.
  4. Dental and Craniofacial Research Institute and Division of Oral Biology, School of Dentistry, University of California, Los Angeles, Los Angeles, California, USA.
  5. Department of Orthopedic Surgery, School of Medicine, University of California, Los Angeles, Los Angeles, California, USA Division of Plastic and Reconstructive Surgery, School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
  6. Dental and Craniofacial Research Institute and Division of Oral Biology, School of Dentistry, University of California, Los Angeles, Los Angeles, California, USA Jonsson Comprehensive Cancer Center and Division of Surgical Oncology, School of Medicine, University of California, Los Angeles, Los Angeles, California, USA [email protected]

Abstract

Recent studies showed that cyclophilin A (CypA) promotes NF-κB/p65 nuclear translocation, resulting in enhanced NF-κB activity and altered expression of its target genes, such as the Sox9 transcriptional factor, which plays a critical role in chondrogenic differentiation and endochondral ossification. In this report, we unveil the role of cyclophilin A in signal-induced chondrogenic differentiation and endochondral ossification. Expression levels of the chondrogenic differentiation markers and transcriptional regulators Sox9 and Runx2 were all significantly lower in cyclophilin A knockdown chondrogenic cells than in wild-type cells, indicating that cyclophilin A plays a functional role in chondrogenic differentiation. In vitro differentiation studies using micromass cultures of mouse limb bud cells further supported the conclusion that cyclophilin A is needed for chondrogenic differentiation. Newborn CypA-deficient pups double stained with alcian blue and alizarin red exhibited generalized, pronounced skeletal defects, while high-resolution micro-computed tomography (microCT) analyses of the femurs and lumbar vertebrae revealed delayed or incomplete endochondral ossification. Comparative histology and immunohistochemistry (IHC) analyses further verified the effects of cyclophilin A deficiency on chondrogenic differentiation. Our results provide evidence for the important contribution of cyclophilin A as a pertinent component acting through NF-κB-Sox9 in regulation of chondrogenesis signaling. These findings are important to better understand signal-induced chondrogenesis of chondrogenic progenitors in physiological and pathophysiological contexts.

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Figure Legend 

cyclophilin A acts through the NF-kB-Sox9 pathway in regulation of chondrogenic differentiation. A. Sox9 is a key molecule for chondrogenic differentiation and cartilage formation and its activity dependent on NF-kB activation. B. RNA interference knock-down of endogenous cyclophilin A (CypA Kd) led to impaired NF-kB activity and significant attenuated NF-kB-dependent gene, such Sox9, expression. D indicates cyclophilin A Kd, blue bold blunt lines indicate inhibition, and red arrows indicate stimulation.

Novel Role Cyclophilin A in Regulation of Chondrogenic Commitment Endochondral Ossification. Global Medical Discovery