The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth
David K. Rhee, … , Matthew L. Warman, John D. Carpten
David K. Rhee, … , Matthew L. Warman, John D. Carpten
Published March 1, 2005
Citation Information: J Clin Invest. 2005;115(3):622-631. https://doi.org/10.1172/JCI22263.
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Article Genetics

The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth

Abstract

The long-term integrity of an articulating joint is dependent upon the nourishment of its cartilage component and the protection of the cartilage surface from friction-induced wear. Loss-of-function mutations in lubricin (a secreted glycoprotein encoded by the gene PRG4) cause the human autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP). A major feature of CACP is precocious joint failure. In order to delineate the mechanism by which lubricin protects joints, we studied the expression of Prg4 mRNA during mouse joint development, and we created lubricin-mutant mice. Prg4 began to be expressed in surface chondrocytes and synoviocytes after joint cavitation had occurred and remained strongly expressed by these cells postnatally. Mice lacking lubricin were viable and fertile. In the newborn period, their joints appeared normal. As the mice aged, we observed abnormal protein deposits on the cartilage surface and disappearance of underlying superficial zone chondrocytes. In addition to cartilage surface changes and subsequent cartilage deterioration, intimal cells in the synovium surrounding the joint space became hyperplastic, which further contributed to joint failure. Purified or recombinant lubricin inhibited the growth of these synoviocytes in vitro. Tendon and tendon sheath involvement was present in the ankle joints, where morphologic changes and abnormal calcification of these structures were observed. We conclude that lubricin has multiple functions in articulating joints and tendons that include the protection of surfaces and the control of synovial cell growth.

Authors

David K. Rhee, Jose Marcelino, MacArthur Baker, Yaoqin Gong, Patrick Smits, Véronique Lefebvre, Gregory D. Jay, Matthew Stewart, Hongwei Wang, Matthew L. Warman, John D. Carpten

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Figure 4

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Histologic and radiographic changes in Prg4–/– mice. (A) H& E-staine...
Histologic and radiographic changes in Prg4–/– mice. (A) H& E-stained sagittal section through the knee joint of a 2-month-old heterozygous mouse (heterozygous mice and wild-type mice have similar histology). Femur (f), tibia (t), and synovium (arrow) are noted. (B) Similar section from a 2-month-old Prg4–/– mouse (magnification in A and B, ×100). Note thickening of the synovium and irregularity and thickening of the cartilage surface. Also note the irregularity in the tibial growth plate. The irregularity of the growth plate is most likely due to a secondary consequence of pathology within the joint, since lubricin is not normally expressed by growth plate chondrocytes (Figure 2B). (C and D) H&E-stained sagittal sections through the knee joint of 9-month-old heterozygous and Prg4–/– mice, respectively (magnification, ×100). Note the preservation of recognizable structures in the heterozygous joint in contrast to the mutant joint. Also note the hyperplastic synovium throughout the joint. (arrows). (E and F) Safranin-O– and fast green–stained sagittal sections through the ankle joint of 7-month-old heterozygous and Prg4–/– mice, respectively (magnification, ×25). Tibia, talus, calcaneus (c), tibial osteophyte (o), tibialis anterior tendon (*) and tendon sheath (ts), and synovium (arrow) are labeled. Note the abnormal appearance of the tendon, tendon sheath, synovium, and osteophyte in the Prg4–/– mouse.