The secreted glycoprotein lubricin protects cartilage surfaces and inhibits synovial cell overgrowth
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
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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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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Effect of reduction and heat denaturation on the ability of lubricin to ...
Effect of reduction and heat denaturation on the ability of lubricin to inhibit Prg4–/– synoviocyte growth. Portions of tissue culture plates (to the right of the dashed lines) were incubated overnight at 37–C with untreated (A), DTT-reduced (B), or heat-denatured (C) lubricin media. After washing off the media with several changes of PBS, we added Prg4–/– synoviocytes to the culture dishes and allowed them to proliferate in growth media for 7 days. Note that cells were able to proliferate on the portions of the plates that contained reduced or heat-denatured lubricin media but not on untreated lubricin media (magnification, ×100). (D–F) Immunodetection of lubricin adhesion to tissue culture plastic. Upper wells were incubated overnight at 37–C with untreated (D), DTT-reduced (E), or heat-denatured (F) control media. Lower wells were incubated overnight at 37–C with untreated (D), DTT-reduced (E), or heat denatured (F) lubricin media. Wells were washed several times with PBS, and we determined lubricin adhesion to the plastic using an anti-lubricin antibody and an HRP-conjugated secondary antibody. Note that lubricin was detected in all 3 lubricin media wells and not in any of the control media wells.