Members of the CCN family of genes include cysteine-rich 61 (CYR61), connective tissue growth factor (CTGF), nephroblastoma overexpressed (NOV), and Wnt-induced secreted proteins (WISP) 1, 2 and 3. CCN proteins play a role in cell differentiation and function, but their expression and function in skeletal tissue is partially understood. We examined the expression and regulation of CCN genes in primary cultures of murine osteoblasts treated with transforming growth factor beta (TGFbeta), bone morphogenetic protein (BMP)-2, or cortisol. Northern blot analysis revealed the presence of CYR61, CTGF, NOV, and WISP 1 and 2 transcripts in murine osteoblasts, but not WISP 3 transcripts. Northern and Western blot analyses revealed that TGF beta, BMP-2, and cortisol increased CYR61 and CTGF mRNA and protein levels. TGF beta decreased NOV and increased WISP 2 mRNA and protein levels, and TGF beta and BMP-2 increased, whereas cortisol decreased WISP 1 mRNA and protein levels. Nuclear run-on assays revealed that TGF beta, BMP-2 and cortisol enhanced CYR61 and CTGF transcription, TGF beta and BMP-2 induced and cortisol suppressed WISP 1, and TGF beta induced WISP 2 transcription. Suppression of NOV transcription could not be detected due to low control levels. In conclusion, five of the six known CCN genes are expressed by osteoblasts and their transcription is regulated by TGF beta, BMP-2 and cortisol.