An in vivoinvestigation of the initiation and progression of subchondral cysts in a rodent model of secondary osteoarthritis

Abstract

IntroductionSubchondral bone cysts (SBC) have been identified in patients with knee osteoarthritis (OA) as a cause of greater pain, loss of cartilage and increased chance of joint replacement surgery. Few studies monitor SBC longitudinally, and clinical research using three-dimensional imaging techniques, such as magnetic resonance imaging (MRI), is limited to retrospective analyses as SBC are identified within an OA patient cohort. The purpose of this study was to use dual-modality, preclinical imaging to monitor the initiation and progression of SBC occurring within an established rodent model of knee OA.MethodsEight rodents underwent anterior cruciate ligament transection and partial medial meniscectomy (ACLX) of the right knee. In vivo 9.4 T MRI and micro-computed tomography (micro-CT) scans were performed consecutively prior to ACLX and 4, 8, and 12 weeks post-ACLX. Resultant images were co-registered using anatomical landmarks, which allowed for precise tracking of SBC size and composition throughout the study. The diameter of the SBC was measured, and the volumetric bone mineral density (vBMD) was calculated within the bone adjacent to SBC. At 12 weeks, the ACLX and contralateral knees were processed for histological analysis, immunohistochemistry, and Osteoarthritis Research Society International (OARSI) pathological scoring.ResultsAt 4 weeks post-ACLX, 75% of the rodent knees had at least 1 cyst that formed in the medial tibial plateau; by 12 weeks all ACLX knees contained SBC. Imaging data revealed that the SBC originate in the presence of a subchondral bone plate breach, with evolving composition over time. The diameter of the SBC increased significantly over time (P = 0.0033) and the vBMD significantly decreased at 8 weeks post-ACLX (P = 0.033). Histological analysis demonstrated positive staining for bone resorption and formation surrounding the SBC, which were consistently located beneath the joint surface with the greatest cartilage damage. Trabecular bone adjacent the SBC lacked viable osteocytes and, combined with bone marrow changes, indicated osteonecrosis.ConclusionsThis study provides insight into the mechanisms leading to SBC formation in knee OA. The expansion of these lesions is due to stress-induced bone resorption from the incurred mechanical instability. Therefore, we suggest these lesions can be more accurately described as a form of OA-induced osteonecrosis, rather than 'subchondral cysts'.

Joint distraction attenuates osteoarthritis by reducing secondary inflammation, cartilage degeneration and subchondral bone aberrant change

“…Higher concentrations of TGF-b1 induced formation of Nestinþ mesenchymal stem cells (MSCs) clusters, leading to formation of marrow osteoid islets accompanied by high levels of angiogenesis 43 . Another study in rat OA model showed that mechanical stress/instability would lead to subchondral stress-induced bone resorption and bone cysts, contributed to OA development 60 . The present findings shows that joint distraction would reduce abnormal bone remodeling in subchondral bone in the rat OA model.…”

“…Further, bone marrow lesions are closely associated with pain and have been implicated to predict the severity of cartilage damage in OA 59 . Recently, several studies indicate that aberrant mechanical stress plays a role in the change of subchondral bone during OA development 43,60 . Zhen and his colleagues demonstrated that in response to abnormal mechanical loading in an OA mouse model, the transforming growth factor b1 (TGF-b1) was activated in subchondral bone.…”

Quantitative histological grading methods to assess subchondral bone and synovium changes subsequent to medial meniscus transection in the rat

“…Using CT scans, subchondral bone has been shown to become more dense in human OA (25–28). Increases in subchondral bone density have also been observed in rodents using a μCT (29–31) and ultrasound (32,33). Using histology from a similar rodent OA model, another study measured TBA according to the ASBMR histomorphometry nomenclature committee (16).…”

Current advances in therapies for osteoarthritis

“…Common findings in the subchondral bone of osteoarthritis patients include microdamage, bone marrow edema-like lesions, and bone cysts [18][19][20]. Genetic predisposition, gender, aging, obesity, physical activity, previous joint injury, joint malalignment, and abnormal joint shape serve as risk factors for osteoarthritis at least partially through their specific influence on subchondral bone [11].…”