Cartilage intermediate layer protein (CILP) is an extracellular matrix protein abundant in cartilaginous tissues. CILP is implicated in common musculoskeletal disorders, including osteoarthritis and lumbar disc disease. Regulation of the CILP gene is largely unknown, however. We have found that CILP mRNA expression is induced by TGF-beta 1 and dependent upon signaling via TGF-beta receptors. TGF-beta 1 induction of CILP is mediated by Smad3, which acts directly through cis-elements in the CILP promoter region. Pathways other than Smad3 also arc involved in TGF-beta 1 induction of CILP. These observations, together with the finding that CILP protein binds and inhibits TGF-beta 1, suggest that CILP and TGF-beta 1 may form a functional feedback loop that controls chondrocyte metabolism. (c) 2006 Elsevier Inc. All rights reserved.