title: Nuclear factor-kappaB p65 facilitates longitudinal bone growth by inducing growth plate chondrocyte proliferation and differentiation and by preventing apoptosis.
abstract: NF-kappaB is a group of transcription factors involved in cell proliferation, differentiation, and apoptosis. Mice deficient in the NF-kappaB subunits p50 and p52 have retarded growth, suggesting that NF-kappaB is involved in bone growth. Yet, it is not clear whether the reduced bone growth of these mice depends on the lack of NF-kappaB activity in growth plate chondrocytes. Using cultured rat metatarsal bones and isolated growth plate chondrocytes, we studied the effects of two NF-kappaB inhibitors (pyrrolidine dithiocarbamate (PDTC) or BAY11-7082 (BAY)), p65 short interference RNA (siRNA), and of the overexpression of p65 on chondrocyte proliferation, differentiation, and apoptosis. To further define the underlying mechanisms, we studied the functional interaction between NF-kappaB p65 and BMP-2 in chondrocytes. PDTC and BAY suppressed metatarsal linear growth. Such growth inhibition resulted from decreased chondrocyte proliferation and differentiation and from increased chondrocyte apoptosis. In cultured chondrocytes, the inhibition of NF-kappaB p65 activation (by PDTC and BAY) and expression (by p65 siRNA) led to the same findings observed in cultured metatarsal bones. In contrast, overexpression of p65 in cultured chondrocytes induced chondrocyte proliferation and differentiation and prevented apoptosis. Although PDTC, BAY, and p65 siRNA reduced the expression of BMP-2 in cultured growth plate chondrocytes, the overexpression of p65 increased it. The addition of Noggin, a BMP-2 antagonist, neutralized the stimulatory effects of p65 on chondrocyte proliferation and differentiation, as well as its anti-apoptotic effect. In conclusion, our findings indicate that NF-kappaB p65 expressed in growth plate chondrocytes facilitates growth plate chondrogenesis and longitudinal bone growth by inducing BMP-2 expression and activity.
authors: Section of Endocrinology and Diabetes, St. Christopherŉs Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania 19134.
authors: Shufang
authors: S
authors: Wu
authors: Section of Endocrinology and Diabetes, St. Christopherŉs Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania 19134.
authors: Janna K
authors: JK
authors: Flint
authors: Section of Endocrinology and Diabetes, St. Christopherŉs Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania 19134.
authors: Geoffrey
authors: G
authors: Rezvani
authors: Section of Endocrinology and Diabetes, St. Christopherŉs Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania 19134. Electronic address: francesco.deluca@drexel.edu.
authors: Francesco
authors: F
authors: De Luca
mesh_terms: D000818:Animals; D017209:Apoptosis; D001846:Bone Development; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000502:physiology*; D001842:Bone and Bones / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D019902:Chondrocytes / Q000378:metabolism*; D017403:In Situ Hybridization; D008954:Models, Biological; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013859:Thiocarbamates / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*
chemical_list: C525719:Bmp2 protein, mouse; C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; C498145:Rela protein, rat; D013859:Thiocarbamates; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; C066229:prolinedithiocarbamate; D011392:Proline; D053148:Caspase 3