Pathophysiological Role of Synovitis in Hemophilic Arthropathy Development: A Two-Hit Hypothesis

Abstract

Despite an increasing access to prophylaxis with clotting factor concentrates, arthropathy still represents the main chronic complication of hemophilia. Whereas previous studies described hemophilic arthropathy (HA) as a degenerative arthropathy, somehow resembling osteoarthritis (OA), most recent evidence suggests that complex inflammatory and immunologic mechanisms are also involved in the pathophysiology of HA. In the present review, we described available data on major mechanisms leading to arthropathic changes in patients with hemophilia, with a specific focus on the role of synovium. The presence of hemosiderin in the joint space induces synovium proliferation, thus leading to formation of several lytic enzymes determining chondrocytes apoptosis and proteoglycans levels reduction. This leads to a direct joint "chemical" damage representing early damages in the pathogenesis of HA (first hit). In parallel, synovial membrane and synovial endothelial cells become a dynamic reservoir of inflammatory cells and mediators, and propagate the inflammatory response (second hit), switching the process from a chemical damage to an inflammatory damage. Overall, consistent data pointed out synovitis as the keystone in HA pathophysiology. This opens novel potential therapeutic targets in this clinical setting.

Keywords: cytokines; hemophilic arthropathy; inflammation; pathophisiology; synovitis.

FIGURE 1

Pathophysiology of hemophilic arthropathy. Type A synoviocytes, after incorporating iron, produce and relapse inflammatory cytokines (IL-1β, IL-6, TNFα) and chemokines (CCL2, CXCL1), leading to migration of polymorphonuclear cells and later, of monocytes and lymphocytes. The consequent inflammatory response promotes:

1. •

   Extracellular matrix degradation.

2. •

   Inhibition of proteoglycan and collagen type II (COL2) synthesis by chondrocytes and induce apoptosis.

3. •

   Expression of metalloprotease (MMP-l, MMP-3, MMP-13, andADAMTS4) that have a pivotal role in catabolic joint processes.

4. •

   Expression of cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE2) involved in development and maintenance of inflammatory process.

5. •

   Neo-angiogenesis, stimulating, both locally and systemically, the release of growth factors like vascular-derived endothelial growth factor (VEGF).

6. •

   Liberation of trombomodulin (TM) by inflammatory cells, TM binds, then activates protein C (PC) inducing factor V (FVa) and FVIIIa degradation.

FIGURE 2

Pathophysiology of hemophilic arthropathy and potential therapeutic approach. Joint bleeding and consequent chemical injury due to iron exposition is the “primwn movens” in development of hemophilic arthropathy leading to inflammation and alteration of natural balance between inflammatory cytokines (IL-1β, IL-6, TNFα, IL-17) and anti-inflammatory cytokines (IL-10, IL-4). Tins leads activation of nuclear transcription factor [nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB)] inducing catabolic process of joint and in turn joint modification. Therapeutic approaches can be direct to stop key point of pathological process: first factor replacement to stop joint bleeding, using anti-inflammatory drugs [cyclooxygenase 2 (COX-2) inhibitors, monoclonal antibodies anti-TNFα, and anti-IL-1β] to balance cytokines pathway.