Lubricin: New Promise for Joint-Preserving Therapy

July 31, 2013

Evidence from animal and human studies supports efforts to use the natural lubricant proteoglycan 4 (lubricin) to protect joints threatened by injury or disease, primarily osteoarthritis. The only thing wanted now is clinical proof of the concept. Gregory Jay MD PhD reviews the history and the potential of this new strategy.

The boundary mode of the synovial joint is lubricated during periods of low sliding speed (less than 0.3 mm/sec)1 and high physiologic loads (approaching 5 mPa)2 by hyaluronic acid and  lubricin, which prevents the pressurized joint surfaces from adhering to each other.3 Boundary lubricants comprise a layer that is less than the height of the asperities (roughness) of the joint surfaces.4,7,8 

Lubricin works together with hyaluronic acid to provide one of the lowest coefficients of friction in all of nature.5-6  A highly O-linked and glycosylated mucinous glycoprotein, lubricin prevents adhesion through steric repulsion, via a layer of brush bristle-like loop and tail structures that are grafted onto the surfaces.7-9 In the case of articular cartilage, surface asperities deform under pressure and are covered by a network of lubricin molecules and conjugates,9 which are secreted onto the articular surface by chondrocytes in the superficial zone10  and into the synovial fluid by synovial fibroblasts.11 (See figure below)
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Lateral and medial joint compartments from the knee of a rat immunoprobed for PRG4 (lubricin) with a monoclonal antibody and developed using goat anti-mouse secondary antibody conjugated to peroxidase, and counterstained with fast green. Lubricin is detected at the cartilage and meniscus surfaces and within the superficial and upper intermediate zones of cartilage. F: femur; T: tibia; m: meniscus.

•    An autosomal recessively inherited disorder of lubricin expression, Camptodactyly arthropathy coxa vara pericarditis (CACP) syndrome, causes severe joint damage in human patients. The condition arises due to truncating mutations that prevent expression of the gene PRG4 (for proteoglycan 4, the chemical name for lubricin). Heterozygote carriers appear phenotypically normal.  Predictably, joint lubrication is abnormal in homozygotes. Synovial fluid obtained from several patients with CACP failed to lubricate a bearing system of latex opposed to polished glass that normal human synovial fluid is able to lubricate.3
       Patients with CACP are usually born with digital flexor contractions and develop early onset severe arthropathy, usually bilaterally in their elbows, knees, hips, and ankles.12,13  They frequently require arthroplasty early in their third decade of life.  Standard anti-inflammatory therapy may be helpful to treat symptoms, and physical therapy is often prescribed. But these patients have unmet medical needs: Immune-modulating therapies are ineffective, because the underlying pathophysiology is due not to autoimmunity but to ongoing mechanical tissue damage.14  

•    A mutant mouse that recapitulates human CACP syndrome has provided a model to study interventions. The creation of Prg4 knockout mice initially provided the opportunity to understand the histology associated with human lubricin deficiency.15 In the absence of lubricin, their articular surfaces are biofouled with albumin and gamma globulin.  In addition, synoviocytes multiply, appear hyperplastic, and encroach upon the articular surface. As these mice age, damage accumulates progressively on their articular surfaces. Excising knee joints from these mice and situating them as the fulcrum of a pendulum has allowed the measurements of whole-joint coefficients of friction, which has confirmed lubricin’s role as an articular lubricant.3
      Preliminary studies are underway introducing recombinant human PRG4 (rhPRG4) into the joints of these Prg4 knockout mice. This will determine whether a temporizing treatment is possible that could be translated to humans. Alternatively, an adeno-associated virus containing the mouse Prg4 gene was recently used to overexpress lubricin in both a mouse injury model and in an aging mouse, with promising results.16

•    Preclinical rodent studies have examined lubricin treatments for the prevention of posttraumatic osteoarthritis (OA). Lubricin is down-regulated in the presence of inflammatory cytokines, including IL-1 and TNF-alpha.17 Rodent OA models have been used to study the effects of intra-articular (IA) injection of rhPRG4, one week following experimental medial meniscectomy18 and anterior cruciate ligament (ACL) transection.19-20 Lubricin supplementation was significantly effective in preserving cartilage in these experiments.18 One study showed significant improvements  in gait symmetry and reduced secretion of urinary CTXII, a biomarker for OA progression.19 Another study of IA lubricin injection, using a forced exercise protocol on rats, showed that those treated with lubricin developed less articular damage than either untreated rats or those injected with IA saline as a placebo. 20

•    Traumatized human joints show reduced levels of lubricin. In a cohort of 33 patients, lubricin levels were significantly reduced in the peri-injury period and up to several months after acute ACL injury, as compared to the aspirated normal contralateral joint.21 In the same study, lubricin concentrations from joint aspirations were near normal almost one year following the injury.

•    Lubricin prevents chondrocyte apoptosis in vitro and in vivo. Using a reciprocating cartilage disc-upon-disc bearing system, cartilage surfaces lubricated by intervening synovial fluid from CACP patients showed significantly more apoptosis of chondrocytes in the superficial and upper intermediate zone than bearings lubricated with normal synovial fluid. (Apoptosis in these zones has also been observed in the Prg4 knockout mice.)22  But supplementing the CACP synovial fluid with purified lubricin prevented this apoptosis in the same cartilage disc bearings, when subjected to mechanical testing.22 These results suggest that adding rhPRG4 to existing viscosupplementation products may provide chondroprotective benefits to patients with a recent traumatic injury, early osteoarthritis, or CACP syndrome.23

Recombinant human PRG4 is a promising biosimilar that requires additional pre-clinical study before its use in joints at risk for osteoarthritis. Potential therapeutic applications would include the traumatized joint, early OA, and synovitis. This form of therapy can be referred to as tribosupplementation.
 

References:

REFERENCES

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