Kartogenin treatment prevented joint degeneration in a rodent model of osteoarthritis: A pilot study

Abstract

Osteoarthritis (OA) is a major degenerative joint disease characterized by progressive loss of articular cartilage, synovitis, subchondral bone changes, and osteophyte formation. Currently there is no treatment for OA except temporary pain relief and endstage joint replacement surgery. We performed a pilot study to determine the effect of kartogenin (KGN, a small molecule) on both cartilage and subchondral bone in a rat model of OA using multimodal imaging techniques. OA was induced in rats (OA and KGN treatment group) by anterior cruciate ligament transection (ACLT) surgery in the right knee joint. Sham surgery was performed on the right knee joint of control group rats. KGN group rats received weekly intra-articular injection of 125 mM KGN 1 week after surgery until week 12. All rats underwent in vivo magnetic resonance imaging (MRI) at 3, 6, and 12 weeks after surgery. Quantitative MR relaxation measures (T 1r and T 2 ) were determined to evaluate changes in articular cartilage. Cartilage and bone turnover markers (COMP and CTX-I) were determined at baseline, 3, 6, and 12 weeks. Animals were sacrificed at week 12 and the knee joints were removed for micro-computed tomography (micro-CT) and histology. KGN treatment significantly lowered the T 1r and T 2 relaxation times indicating decreased cartilage degradation. KGN treatment significantly decreased COMP and CTX-I levels indicating decreased cartilage and bone turnover rate. KGN treatment also prevented subchondral bone changes in the ACLT rat model of OA. Thus, kartogenin is a potential drug to prevent joint deterioration in post-traumatic OA. Keywords: Osteoarthritis; kartogenin; cartilage; subchondral bone; 7T MRI Osteoarthritis (OA) is a common cause of pain and disability, and is expected to be the 4th leading cause of physical disability by the year 2020.1 OA affects the hip, knee, spine, hand, and shoulder joints; however, knee OA results in the most significant morbidities including life-long pain and disability.2 OA is characterized by progressive degeneration of cartilage, subchondral bone changes such as sclerosis, subchondral bone cysts, osteophytes, and synovitis.3,4 Currently, no disease-modifying OA drugs (DMOAD) have been approved by the FDA, to slow or stop the progression of OA.5 Advanced quantitative medical imaging modalities and processing techniques promises potential methods to quantify the effect of DMOAD on articular cartilage and subchondral bone tissues in vivo. 6,7 While the cause of OA remains unclear, it is well established that cartilage changes related to the chondrocyte lifespan or metabolism or both is a major part of the disease process. 8 Chondrocytes are the only cell type found in the cartilage matrix and occupy less than 2% of the cartilage volume.9 Chondrocytes are derived from mesenchymal stromal cells, therefore, the concept of stem cell therapies to prevent or treat OA through either replacing chondrocytes or through paracrine actions influencing chondrocyte metabolism are being studied extensively.10,11 St...

Comparison of micro-CT post-processing methods for evaluating the trabecular bone volume fraction in a rat ACL-transection model

“…The results with this method identified bone loss in the ACL transected knee, suggesting a global response of the bone to joint unloading, which agree with previous reports of bone loss in the medial compartment of the tibial epiphyses with ACL transection (Maerz et al, 2016; Mohan et al, 2016; Proffen et al, 2016). Previous studies suggest that decreases in BV/TV correspond to unloading of the ACL transected limb or due to an inflammatory response that affects bone resorption (Jay et al, 2012; Maerz et al, 2016; Proffen et al, 2016).…”

“…Volumetric shapes include strips (Batiste et al, 2004), cylinders (Boudenot et al, 2014; Iijima et al, 2015; Intema et al, 2010; McErlain et al, 2008; Sniekers et al, 2008), and cubes (Florea et al, 2015). Sizes vary from small 2 x 2 x 4mm 3 cubes (Florea et al, 2015) to large anatomical contours that include the medial or lateral compartments of the tibia (Hamann et al, 2012; Maerz et al, 2016; Mohan et al, 2016). ROI location and number varies from a single load bearing location (Batiste et al, 2004; Boudenot et al, 2014) to multiple locations throughout the compartment (McErlain et al, 2008).…”

Kartogenin Enhances Collagen Organization and Mechanical Strength of the Repaired Enthesis in a Murine Model of Rotator Cuff Repair

“…The chondrogenesis inductive properties of KGN have been used in animal models to mimic the structural changes seen in overuse tendinopathy, 23 augment microfracture for the treatment of full-thickness cartilage defects, 9 prevent the progression of osteoar-thritis, 6,8 and induce the formation of meniscus-like tissue. 24 However, in our study, we found that KGN-treated animals had a lower percentage of Alcian blue—positive areas (indicating fibrocartilage formation) within the repaired enthesis compared with controls.…”

“…5 Kartogenin (KGN), a small synthetic heterocyclic compound (Fig 1), has been reported to induce chondrogenic differentiation of mesenchymal stem cells and tendon stem cells. 6,7, The chondrogenesis induction properties of KGN have been investigated as a potential chondroprotective therapy for osteoarthritis 6,8 and as a supplement to microfracture for the treatment of full-thickness cartilage defects. 9 Recently, Wang et al 7,10,11 have studied the use of KGN, in combination with platelet-rich plasma (PRP), to facilitate fibrocartilage formation at the interface between tendon and bone, in an attempt to recreate the fibrocartilage zones of the native enthesis.…”

Application of kartogenin for musculoskeletal regeneration

“…Currently the only definitive treatment available for OA is end‐stage joint replacement surgery. The regenerative effect of KGN would, if successful, add substantially to the armamentarium of current IA therapeutics, which principally address only inflammation …”