Fight Aging!

Researchers here find that inhibition of Wnt signaling can improve the state of cartilage and joint function in a mouse model of osteoathritis. Wnt and its closely related proteins are a complex topic, but the short version is that they are involved in the regulation of growth, regeneration, and embryonic development. They are also significant in cancer, as well as in other, less dramatic ways in which regeneration can run wild or fail, producing fibrosis and functional problems rather than a useful restoration of tissue. Numerous research groups are investigating ways in which Wnt signaling can be adjusted to produce beneficial effects such as enhanced healing, or a reduction in function damage to tissues following injury. This is a representative example.

Wnt family proteins are a class of morphogens associated with embryonic skeletal formation, tissue repair, fibrosis, and joint homeostasis. Wnts regulate multiple signaling cascades, including the β-catenin-dependent (canonical) pathway. The Wnt/β-catenin pathway, which is typically quiescent in many adult organs, is activated in response to injury. Its role in tissue repair and regeneration is complex and incompletely understood, although an increasing body of data suggests that its activation augments fibrotic repair. Our group recently published studies demonstrating that brief therapeutic Wnt inhibition following both full thickness cutaneous or ischemic cardiac injury resulted in improved regenerative repair with less fibrosis.

Osteoarthritis (OA) is a degenerative joint disease typically characterized by articular cartilage degeneration, bone remodeling, and osteophytosis as well as fibrosis and hyperplasia of the synovial membrane. In OA pathogenesis, activation of canonical Wnt signaling is observed in both articular cartilage and synovium following injury, with increased expression of both Wnt ligands and target genes. Induced overexpression of β-catenin within mature chondrocytes has been shown to exacerbate cartilage degeneration, chondrocyte hypertrophy, and expression of matrix proteases. However, significant or complete ablation of β-catenin in chondrocytes also results in the deleterious effect of chondrocyte apoptosis. Moreover, increased canonical Wnt expression in the synovium resulted in strong induction of cartilage pathology. Although the sum of the published data using genetic modulation of Wnt suggests deleterious effects of Wnt on OA pathogenesis, there is little known about the therapeutic effect of inhibiting the Wnt pathway within the context of disease.

Multiple Wnt inhibitory therapeutics are being investigated at various stages of clinical development due to Wnt pathway activation, not only in fibrotic diseases, but also cancers. We sought to study Wnt signaling and the effect of local therapeutic Wnt inhibition in a murine model of traumatic OA caused by destabilization of the medial meniscus (DMM). To assess the effect of Wnt inhibition on OA progression, we injected the small-molecule Wnt inhibitor, XAV-939, in the intra-articular space. We further studied the cell-specific effects of Wnt modulation in vitro using primary human synovial fibroblasts and chondrocytes in order to understand the cellular basis for the disease-modifying effects.

Our study demonstrated that traumatic joint injury through DMM surgery induced robust activation of canonical Wnt signaling, most striking in the synovium, and this upregulation was downregulated with intermittent (every 10 days), local (intra-articular) treatment using a small-molecule Wnt inhibitor, resulting in amelioration of both synovitis and cartilage loss. An important advantage of identifying therapeutic benefits with local administration is avoiding systemic effects of Wnt inhibition on Wnt-dependent tissues, such as intestinal stem cell/intestinal turnover, hematopoiesis, and bone density. The use of small-molecule Wnt inhibitors bypasses the restrictions of genetic approaches by targeting the entire injury milieu, rather than a particular cell type, as is the case in genetic models. Additionally, since different cell types exhibit different levels of Wnt activation and sensitivity to Wnt inhibition, one can also fine-tune the degree and timing of Wnt inhibition using dosing strategies that are calibrated.

Link: https://doi.org/10.1172/jci.insight.96308