Early genetic restoration of lubricin expression in transgenic mice mitigates chondrocyte peroxynitrite release and caspase-3 activation

Abstract

Objective This study investigated the ability of endogenous lubricin secretion to restore joint health following a brief < 21 day, postnatal lubricin-null state, in a C57BL/6J Prg4 gene trap mouse under the control of cre-recombinase. Previously we showed that re-expression of lubricin at 21 days was partly restorative of joint lubrication. Design The tibio-femoral joints of adult C57BL/6J mice containing lubricin, lacking lubricin, and postnatally lacking lubricin until restoration of lubricin expression at 7 days or 14 days of age were evaluated ex vivo. At 8-weeks of age, whole joint coefficient of friction (COF), and caspase-3 activation were measured and the tibial-femoral joints histologically analyzed for degenerative changes, following progressive cyclic loading. The peroxynitrite content of femoral head cartilage from these mice prior to cyclic loading was measured. Results Mice that underwent gene recombination at 7 and 14 days of age did not reestablish low COF as joint cycling time increased and were histopathologically indistinguishable from the joints of lubricin-null littermates. However, cartilage from tibio-femoral joints that underwent recombination at 7 and 14 days of age had significantly fewer caspase-3 positive cells and significantly reduced peroxynitrite content compared to lubricin-null littermates. Conclusions The biological effects of lubricin, which include limiting inflammation via peroxynitrite production and caspase-3 activation, may be achieved without completely restituting low COF. However, fully recapitulating low COF may require undamaged cartilage surfaces or absence of biofouling, which may interfere with the activity of lubricin.

BMP9 stimulates joint regeneration at digit amputation wounds in mice

“…To investigate if Prg4 is required for BMP9-induced cavitation, we performed P2 amputations and BMP9 treatment in the Prg4 −/− mouse 22 . Prg4 −/− mice form joints indicating that it is not required for joint development; however, mutant joints have reduced articular cartilage surfaces and display a joint degeneration phenotype 22,23 . Digits of Prg4 −/− and Prg4 +/− neonates were amputated and treated with BMP9 or BSA after wound closure.…”

Proteoglycan-4 regulates fibroblast to myofibroblast transition and expression of fibrotic genes in the synovium

“…PRG4 is secreted from synovial fibroblasts and superficial zone chondrocytes and is found adsorbed on articular surfaces and the synovial membrane in addition to its presence in SF [52,53]. PRG4 has a multifaceted role in the joint and one aspect of its role is to provide boundary lubrication, to prevent friction-induced mitochondrial dysregulation and chondrocyte apoptosis [54][55][56]. Synthesis of PRG4 by cartilage and synovium was reduced in posttraumatic OA (PTOA) animal models and inflammatory cytokines, e.g., IL-1β reduced PRG4 secretion by synovial fibroblasts while TGF-β produced an opposite effect [57][58][59].…”

Proteoglycan-4 Regulates Fibroblast to Myofibroblast Transition and Expression of Fibrotic Genes in the Synovium

“…PRG4 is secreted from synovial fibroblasts and superficial zone chondrocytes and is found adsorbed on articular surfaces and the synovial membrane in addition to its presence in SF [53,54]. PRG4 has a multifaceted role in the joint and one aspect of its role is to provide boundary lubrication, to prevent friction-induced mitochondrial dysregulation and chondrocyte apoptosis [55][56][57]. Synthesis of PRG4 by cartilage and synovium was reduced in posttraumatic OA (PTOA) animal models and inflammatory cytokines e.g.…”