Cartilage is one of the least regenerative tissues in the body, and thus damage and aging leads to osteoarthritis, disability, and joint pain. There is considerable interest in finding ways to effectively repair or replace cartilage, provoke existing tissue into greater regenerative capacity, or adjust cellular biochemistry to make cartilage more resilient to damage and cell death. Here, researchers report on the manipulation of a regulatory protein in cartilage cells, NR0B2, also known as SHP, that is reduced in expression as osteoarthritis progresses, and appears to be protective. It might prove to be a useful target to slow the progression of cartilage loss and osteoarthritis.
Osteoarthritis (OA), characterised by cartilage destruction, is the most common degenerative joint disease. However, no effective disease-modifying OA therapy is currently available. Herein, we report orphan nuclear receptor small heterodimer partner (SHP, NR0B2) as a novel catabolic regulator of OA pathogenesis. NR0B2 expression was markedly downregulated in cartilage from patients with OA.
Global or chondrocyte-specific Nr0b2 deletion in male mice exacerbated OA-related pain and structural changes following surgical destabilization of the medial meniscus, accompanied by increased matrix metalloproteinase (MMP)-3 and MMP-13 expression in chondrocytes. Conversely, adeno-associated virus-mediated Nr0b2 overexpression in knee joints of male mice protected against accelerated knee OA caused by Nr0b2 deficiency. Mechanistically, NR0B2 inhibited IKKβ kinase activity via IKK complex interaction, downregulating NF-κB signalling.
Our results demonstrate that NR0B2 has a chondroprotective role in OA progression by regulating matrix-degrading enzymes in an IKKβ/NF-κB-dependent manner, and gene therapy targeting Nr0b2 may be a promising therapeutic strategy for OA.
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