Osteoarthritis (OA) is a total joint disease characterized by articular cartilage degradation, synovial inflammation, meniscus degeneration, subchondral bone sclerosis, osteophyte formation, and joint pain. It afflicts nearly 1/4 of the US population resulting in healthcare expenditures exceeding $185 billion annually. Despite the severity and impact of OA on individuals and our health care system, only recently have there been advances in understanding the molecular, cellular and tissue events underlying OA development. It is well established that inappropriate expression and activation of catabolic enzymes underlies the joint cartilage destruction observed in OA, however the precise molecular mechanisms responsible for promoting joint cartilage catabolism is not well understood, nor is there a defined understanding of the molecular mediators of OA-associated pain. Recently an up-regulation in the NOTCH signaling pathway has been documented in human and murine post-traumatic OA (PTOA), suggesting a connection between aberrant NOTCH signaling and OA. Using cartilage-specific loss-of-function and gain-of-function mouse genetic approaches, we demonstrated that physiological NOTCH signaling is required for long-term maintenance of the joint cartilages, however enhanced NOTCH signaling leads to a progressive OA pathology and chronic pain. We further utilized RNA-sequencing, immunohistochemistry (IHC), and biochemical approaches to identify several NOTCH targets potentially responsible for NOTCH-mediated joint cartilage catabolism and OA-associated pain; factors that are also dysregulated during OA progression in both mice and humans. Our published and preliminary data identified IL-6/JAK/STAT and nerve growth factor (NGF) signaling as highly relevant NOTCH targets that may significantly contribute to joint cartilage catabolism and pathological pain observed in NOTCH-induced OA and PTOA. Therefore, we will test the overarching hypothesis that pathologic NOTCH signaling activation promotes IL-6/JAK/STAT and NGF signaling to induce joint cartilage catabolism and pain in OA. A variety of in vivo and in vitro approaches will identify the NOTCH pathway and critical downstream effectors (IL-6/JAK/STAT and NGF) as important regulators of OA-associated cartilage catabolism and pain, while simultaneously testing NOTCH neutralizing antibodies as a translational disease modifying osteoarthritis drug (DMOAD) therapy.
Enhanced NOTCH pathway activation is observed in human and murine osteoarthritic joint cartilages. Using genetic mouse models, we demonstrate that cartilage-specific NOTCH activation induces the OA-related phenotypes of joint cartilage catabolism and pain, while also up-regulating the IL-6/JAK/STAT and NGF signaling pathways. This proposal will determine the precise NOTCH signaling targets responsible for NOTCH-mediated joint cartilage catabolism and OA- associated pain utilizing both injury induced and NOTCH-induced OA mouse models, while simultaneously testing NOTCH neutralizing antibodies as a translational disease modifying osteoarthritis drug (DMOAD) therapy.
|Dar, Qurratul-Ain; Schott, Eric M; Catheline, Sarah E et al. (2017) Daily oral consumption of hydrolyzed type 1 collagen is chondroprotective and anti-inflammatory in murine posttraumatic osteoarthritis. PLoS One 12:e0174705|
|Lawal, Rialnat A; Zhou, Xichao; Batey, Kaylind et al. (2017) The Notch Ligand Jagged1 Regulates the Osteoblastic Lineage by Maintaining the Osteoprogenitor Pool. J Bone Miner Res 32:1320-1331|
|Cao, Chike; Ren, Yinshi; Barnett, Adam S et al. (2017) Increased Ca2+ signaling through CaV1.2 promotes bone formation and prevents estrogen deficiency-induced bone loss. JCI Insight 2:|
|Shang, Xifu; Wang, Jinwu; Luo, Zhengliang et al. (2016) Notch signaling indirectly promotes chondrocyte hypertrophy via regulation of BMP signaling and cell cycle arrest. Sci Rep 6:25594|
|Rutkowski, Timothy P; Kohn, Anat; Sharma, Deepika et al. (2016) HES factors regulate specific aspects of chondrogenesis and chondrocyte hypertrophy during cartilage development. J Cell Sci 129:2145-55|
|Liu, Z; Ren, Y; Mirando, A J et al. (2016) Notch signaling in postnatal joint chondrocytes, but not subchondral osteoblasts, is required for articular cartilage and joint maintenance. Osteoarthritis Cartilage 24:740-51|
|Wang, Cuicui; Inzana, Jason A; Mirando, Anthony J et al. (2016) NOTCH signaling in skeletal progenitors is critical for fracture repair. J Clin Invest 126:1471-81|
|Zhang, Yongchun; Sheu, Tzong-jen; Hoak, Donna et al. (2016) CCN1 Regulates Chondrocyte Maturation and Cartilage Development. J Bone Miner Res 31:549-59|
|Hamada, Daisuke; Maynard, Robert; Schott, Eric et al. (2016) Suppressive Effects of Insulin on Tumor Necrosis Factor-Dependent Early Osteoarthritic Changes Associated With Obesity and Type 2 Diabetes Mellitus. Arthritis Rheumatol 68:1392-402|
|Zhang, Hengwei; Sun, Wen; Li, Xing et al. (2016) Use of Hes1-GFP reporter mice to assess activity of the Hes1 promoter in bone cells under chronic inflammation. Bone 90:80-9|
Showing the most recent 10 out of 23 publications