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Loss of CDKN2B Promotes Fibrosis via Increased Fibroblast Differentiation Rather Than Proliferation.
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease characterized by excessive scarring and fibroblast activation. We previously showed that fibroblasts from patients with IPF are hypermethylated at the CDKN2B gene locus, resulting in decreased CDKN2B expression. Here, we examine how diminished CDKN2B expression in normal and IPF fibroblasts affect fibroblast function, and how loss of CDKN2B contributes to IPF pathogenesis. We first confirmed that protein expression of CDKN2B was diminished in IPF lungs in situ. Loss of CDKN2B was especially notable in regions of increased myofibroblasts and fibroblastic foci. The degree of CDKN2B hypermethylation was particularly elevated in patients with radiographic honeycombing, a marker of more advanced fibrosis, and increased DNA methylation correlated with decreased expression. Although CDKN2B is traditionally considered a cell cycle inhibitor, loss of CDKN2B did not result in an increase in fibroblast proliferation, but instead was associated with an increase in myofibroblast differentiation. An increase in myofibroblast differentiation was not observed when CDKN2A was silenced. Loss of CDKN2B was associated with an increase in the transcription factors serum response factor and myocardin-related transcription factor A, and overexpression of CDKN2B in IPF fibroblasts inhibited myofibroblast differentiation. Finally, decreased CDKN2B expression was noted in fibroblasts from a murine model of fibrosis, and Cdkn2b-/- mice developed greater histologic fibrosis after bleomycin injury. These findings identify a novel function for CDKN2B that differs from its conventional designation as a cell cycle inhibitor and demonstrate the importance of this protein in pulmonary fibrosis.
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