Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 115, Issue 3, Pages 622-631Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200522263
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Funding
- NIAMS NIH HHS [R01 AR046249, AR46249, AR050180, R01 AR050180] Funding Source: Medline
- NIA NIH HHS [K08AG/AR01008] Funding Source: Medline
- NICHD NIH HHS [T32 HD007104, T32 HD007518, HD07518, HD07104] Funding Source: Medline
- NIGMS NIH HHS [GM08613, GM07250, T32 GM008613, T32 GM007250] Funding Source: Medline
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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.
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