Cdc42 Is Essential for Both Articular Cartilage Degeneration and Subchondral Bone Deterioration in Experimental Osteoarthritis

Abstract

Cdc42, a member of Rho family small guanosine triphosphatases (GTPases), is critical for cartilage development. We investigated the roles of Cdc42 in osteoarthritis and explored the potential mechanism underlying Cdc42-mediated articular cartilage degeneration and subchondral bone deterioration. Cdc42 is highly expressed in both articular cartilage and subchondral bone in a mouse osteoarthritis model with surgical destabilization of the medial meniscus (DMM) in the knee joints. Specifically, genetic disruption of Cdc42, knockdown of Cdc42 expression, or inhibition of Cdc42 activity robustly attenuates the DMM-induced destruction, hypertrophy, high expression of matrix metallopeptidase-13 and collagen X, and activation of Stat3 in articular cartilages. Notably, genetic disruption of Cdc42, knockdown of Cdc42 expression or inhibition of Cdc42 activity significantly restored the increased numbers of mesenchymal stem cells, osteoprogenitors, osteoblasts, osteoclasts, and neovascularized vessels, the increased bone mass, and the activated Erk1/2, Smad1/5 and Smad2 in subchondral bone of DMM-operated mice. Mechanistically, Cdc42 mediates interleukin-1β-induced interleukin-6 production and subsequent Jak/Stat3 activation to regulate chondrocytic inflammation, and also lies upstream of Erk/Smads to regulate subchondral bone remodeling during transform growth factor-β1 signaling. Cdc42 is apparently required for both articular cartilage degeneration and subchondral bone deterioration of osteoarthritis, thus, interventions targeting Cdc42 have potential in osteoarthritic therapy. © 2018 American Society for Bone and Mineral Research.

Angiogenesis stimulated by elevated PDGF-BB in subchondral bone contributes to osteoarthritis development

“…A previous study reported that leucine rich alpha-2-glycoprotein 1 (LRG1), which regulates epithelial-mesenchymal transition and angiogenesis in colorectal cancer, may regulate pathogenic subchondral bone angiogenesis because increased LRG1 was found in the subchondral bone and AC in anterior cruciate ligament transection (ACLT) mice (57). The increased LRG1 in subchondral bone was detected at 30 days after ACLT surgery, when AC degeneration had already occurred (16,34), suggesting that LRG1 may regulate subchondral bone angiogenesis at a relatively late stage of posttraumatic osteoarthritis. A recent study by Lu et al, using the DMM OA mouse model, demonstrated that activated mTOR complex 1 in the hypertrophic chondrocytes in AC mediated the production of VEGF from the chondrocytes, resulting in subchondral bone angiogenesis at 5 weeks after DMM surgery (32).…”

“…This osteochondral angiogenesis not only stimulates early osteophyte development and ossification in the cartilage but also causes innervation of AC, causing joint pain. Consistently, animal studies have shown that aberrant subchondral bone angiogenesis coupled with osteogenesis may contribute to the development of subchondral bone marrow lesions, increased subchondral bone plate thickness, and eventual AC damage (16,(32)(33)(34)(35). However, the key factor(s) for the development of pathological subchondral bone angiogenesis and the main source of the factor(s) during osteoarthritis development remain unclear.…”

“…However, treatments targeting only the signaling mechanisms responsible for AC degeneration may be insufficient to halt disease progression (7,(12)(13)(14). Recent evidence suggests that pathological alterations in subchondral bone also contribute to osteoarthritis development (15)(16)(17)(18)(19)(20)(21)(22)(23).…”

“…Increases in osteoclast activity and turnover rate in subchondral bone in response to aberrant mechanical loading are often among the first detectable osteoarthritis alterations (16,(36)(37)(38). Osteoclasts are derived from bone marrow monocytes/macrophages.…”

Etoricoxib decreases mouse subchondral bone mass and biomechanical properties in early osteoarthritis

“…Previous studies on OA mainly focused on articular cartilage degeneration. However, the differences between the results of preclinical research and clinical medication of OA have shown that targeting articular cartilage alone is not enough to prevent the progress of OA [3]. Not only cartilage, but also subchondral bone plays an important role in the pathogenesis of OA.…”