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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Figure 5

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Histologic changes in the articular cartilage and synovium of Prg4–/– mi...
Histologic changes in the articular cartilage and synovium of Prg4–/– mice. H&E-stained sagittal section through the tibia of 7-day-old heterozygous (A) and Prg4–/– (D) mice, 2-month-old heterozygous (B) and Prg4–/– (E) mice, and 9-month-old heterozygous (C) and Prg4–/– (F) mice (magnification in A–F, ×400). Note that flattened superficial zone chondrocytes are present in both the heterozygous and Prg4–/– cartilage of the 7-day-old mice (arrows) (A and D). Flattened superficial zone chondrocytes are present in both the 2-month old and 9-month old (B and C) heterozygous mice (arrow) but are lost in the 2-month-old and 9-month-old Prg4–/– mice (E and F). Also note the presence of a thick layer of weakly stained material at the cartilage surface (bracket) (E). (G–L) H&E-stained section of knee synovium from 15-day-old wild-type (G) and Prg4–/– (H) mice (magnification, ×400), 2-month-old heterozygous (I) and Prg4–/– (J) mice (magnification, ×400), and 6-month-old heterozygous (K) and Prg4–/– (L) mice (magnification, ×200). Note the progressive hyperplasia and thickening (brackets) of the intimal and subintimal layers in the Prg4–/– mice (H, J, and L).