Wnt9a, a secreted ligand, drives both the canonical (β-catenin dependent) and non-canonical (β-catenin independent) Wnt signaling pathways. It plays crucial roles in cell fate determination, embryonic patterning, bone development, and organogenesis, especially during hematopoietic stem cell development, proper bone formation, and chondrogenesis [2]. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in understanding its functions.

In renal fibrosis, Wnt9a promotes the process by accelerating cellular senescence in tubular epithelial cells. High levels of Wnt9a are expressed in tubular cells of humans with nephropathies and in mouse models of CKD, correlating with renal fibrosis and the expression of senescence-related protein p16INK4A. Ectopic expression of Wnt9a after ischemia-reperfusion injury exacerbates renal fibrosis and tubular senescence, while shRNA-mediated knockdown of Wnt9a represses renal fibrosis in vivo and inhibits the growth of senescent tubular epithelial cells in culture. Also, Wnt9a-induced renal fibrosis was inhibited by shRNA-mediated silencing of p16INK4A in the IRI mouse model [1].

In the context of osteoarthritis, conditional loss of Wnt9a in the Prx1-Cre expressing limb mesenchyme or Prg4-CreER expressing cells predisposes mice to develop spontaneous OA-like changes with age, and the trabecular bone volume is altered in these mice [3]. In a chronic TNF-dependent rheumatoid arthritis (RA) mouse model, loss of Wnt9a leads to an aggravation of disease progression with enhanced pannus formation and joint destruction, suggesting a specific role for Wnt9a in TNF-triggered RA [4].

In summary, Wnt9a is essential in multiple biological processes including hematopoiesis, bone development, and organogenesis. Through KO/CKO mouse models, its significant roles in diseases like renal fibrosis, osteoarthritis, and TNF-triggered rheumatoid arthritis have been revealed. These findings enhance our understanding of the biological functions of Wnt9a and its implications in disease mechanisms, potentially providing new insights for disease treatment and prevention.