One of two chondrocyte‐expressed isoforms of cartilage intermediate‐layer protein functions as an insulin‐like growth factor 1 antagonist

Objective Aging and osteoarthritic (OA) cartilage commonly demonstrate enhanced expression of the large, transforming growth factor β (TGFβ)–inducible glycoprotein cartilage intermediate‐layer protein (CILP) as well as enhanced extracellular inorganic pyrophosphate (PPi) that promotes the deposition of calcium pyrophosphate dihydrate crystals. In normal chondrocytes, TGFβ induces elevated chondrocyte extracellular PPi. Insulin‐like growth factor 1 (IGF‐1) normally blocks this response and reduces extracellular PPi. However, chondrocyte resistance to IGF‐1 is observed in OA and aging. Because CILP was reported to chromatographically fractionate with PPi‐generating nucleotide pyrophosphatase phosphodiesterase (NPP) activity, it has been broadly assumed that CILP itself has NPP activity. Our objective was to directly define CILP functions and their relationship to IGF‐1 in chondrocytes. Methods Using primary cultures of articular chondrocytes from the knee, we defined the function of the previously described CILP (CILP‐1) and of a recently described 50.6% identical protein that we designated the CILP‐2 isoform. Results Both CILP isoforms were constitutively expressed by primary cultured articular chondrocytes, but only CILP‐1 expression was detectable in cultured knee meniscal cartilage cells. Neither CILP isoform had intrinsic NPP activity. But CILP‐1 blocked the ability of IGF‐1 to decrease extracellular PPi, an activity specific for the CILP‐1 N‐terminal domain. The CILP‐1 N‐terminal domain also suppressed IGF‐1–induced (but not TGFβ‐induced) proliferation and sulfated proteoglycan synthesis, and it inhibited ligand‐induced IGF‐1 receptor autophosphorylation. Conclusion Two CILP isoforms are differentially expressed by chondrocytes. Neither CILP isoform exhibits PPi‐generating NPP activity. But, increased expression of CILP‐1, via N‐terminal domain–mediated inhibitory effects of CILP‐1 on chondrocyte IGF‐1 responsiveness, could impair chondrocyte growth and matrix repair and indirectly promote PPi supersaturation in aging and OA cartilage.