WNK2 variants associated with familial osteoarthritis alter the chondrocyte response to hyperosmotic stress

Chondrocytes of the synovial joint sense and respond to changes in osmolarity to maintain joint homeostasis. We hypothesised that an abnormal response to osmotic stress is a contributing factor to loss of joint homeostasis and the development of osteoarthritis (OA). Our goal was to identify whether genetic variants affecting the response to osmotic stress were associated with susceptibility to OA.

Genomic analysis of independent families with dominant inheritance of OA revealed novel WNK2 coding variants that segregated with occurrence of OA. WNK2 expression was examined by immunohistochemistry on normal and osteoarthritic tissue isolated from humans and mice. Wild type (WT) and variant WNK2 functions were analysed by overexpression effects in immortalised and primary human chondrocytes; loss-of-function effects were analysed in WNK2 mutant cells. Transcriptomic analyses were used to identify genes and pathways dependent on WNK2 function and hyperosmotic stress.

We identified novel coding variants of WNK2 associated with familial erosive hand OA and foot OA. WNK2 is expressed in chondrocytes and its expression is highly elevated in end-stage human and mouse OA joints. When challenged by hyperosmotic stress, chondrocytes initiate a remodelling response, altering expression of both anabolic and catabolic genes and pathways. However, the combination of elevated WNK2 expression and hyperosmotic stress promotes a WNK2-dependent OA-associated transcriptional response that is exacerbated by expression of the OA-associated WNK2 variants.

Our data indicate elevated WNK2 signalling is associated with heightened susceptibility to OA. We hypothesise the synergistic effects of hyperosmotic stress and high WNK2 activity promote the development of OA.