Cbfβ mediates articular cartilage regeneration and repair in aging

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The long term goal of this study is to understand the mechanisms mediating osteoarthritis in aging. The specific goal of this study is to characterize the mechanism underlying how Cbfβ mediates cartilage regeneration and repair in osteoarthritis. Osteoarthritis (OA) is the most common form of arthritis affecting the knees, hips and spines, inflicting pain and physical limitation on over 70% of Americans between the age of 55 and 70. Current therapeutic options for OA are still limited to pain management and surgical intervention representing a significant concern in the aging population. Recent studies have shed light on the nature of OA genetic susceptibility and confirmed a number of candidate genes involved in the damage of the synovium, articular cartilage, and subchondral bone in OA pathogenesis, including Wnt signaling. However, the root causes of the disease remain unclear. Having investigated the gene expression patterns between OA patients and normal donors, and in combining with the known regulation data, Qingyou et al. identified a number of transcriptional factors and other genes which may play important roles in the development of OA including Core-binding factor beta (Cbfβ). The PI’s lab has extensively study Cbfβ function in osteoblasts and chondrocytes during mouse skeletal development. Nevertheless, the function of Cbfβ in OA pathogenesis and articular cartilage regeneration and repair remains unclear. In order to study OA pathogenesis in chondrocyte- specific Cbfβ deficient mice, we generated the inducible conditional knockout (CKO) Cbfβf/fCol2α1-CreER mice using Tamoxifen injections. We discovered that Cbfβ CKO mice developed spontaneous OA at the age of 3.5 months, showing severe OA phenotype at the shoulders, knees, hips and spines. Our data demonstrated that Wnt canonical signaling was down-regulated and Yap expression was up-regulated in Cbfβf/fCol2α1-CreER mice and that Cbfβ overexpression mediated by AAV-CMV-Cbfβ has significant protection against OA. Based on our preliminary data, we hypothesize that deficiency of Cbfβ is one of the main causes of cartilage degeneration in OA and aging and that overexpression of Cbfβ enhances cartilage regeneration and repair in OA by regulating Wnt signaling and Yap signaling. We will test this hypothesis through three specific aims. In Aim 1, we will determine the roles of Cbfβ in aging articular chondrocyte homeostasis through extensive phenotypic analyses of adult and aged, female and male Cbfβf/fCol2α1-CreER mice in physiological and pathological conditions. In Aim 2, we will define the function of Cbfβ in cartilage regeneration and repair and preventing OA genesis in aging by characterizing Cbfβ gain-of-function mouse model. We will dissect the mechanism underlying how Cbfβ regulates Wnt and Yap signaling during chondrogenesis and articular cartilage regeneration and repair in Aim 3. The proposed study will provide important insights into the roles of Cbfβ in OA by elucidating the mechanism by which Cbfβ regulates Wnt and Yap signaling in articular cartilage regeneration and repair. A multidisciplinary research team been established to achieve the research goals.