Early signs of osteoarthritis in differing rat osteochondral defects.

Preclinical models of osteochondral defects (OCDs) are fundamental test beds to evaluate treatment modalities before clinical translation. To increase the rigor and reproducibility of translational science for a robust "go or no-go," we evaluated disease progression and pain phenotypes within the whole joint for two OCD rat models with same defect size (1.5 x 0.8 mm) placed either in the trochlea or medial condyle of femur. Remarkably, we only found subtle transitory changes to gaits of rats with trochlear defect without any discernible effect to allodynia. At 8-weeks post-surgery, anatomical evaluations of joint showed early signs of osteoarthritis with EPIC-microCT. For the trochlear defect, cartilage attenuation was increased in trochlear, medial, and lateral compartments of the femur. For condylar defect, increased cartilage attenuation was isolated to the medial condyle of the femur. Further, the medial ossicle showed signs of deterioration as indicated with decreased bone mineral density and increased bone surface area to volume ratio. Thus, OCD in a weight-bearing region of the femur gave rise to more advanced osteoarthritis phenotype within a unilateral joint compartment. Subchondral bone remodeling was evident in both models without any indication of closure of the articular cartilage surface. We conclude that rat OCD, placed in the trochlear or condylar region of the femur, leads to differing severity of osteoarthritis progression. As found herein, repair of the defect with fibrous tissue and subchondral bone is insufficient to alleviate onset of osteoarthritis. Future therapies using rat OCD model should address joint osteoarthritis in addition to repair itself.

pH-sensing G protein-coupled orphan receptor GPR68 is expressed in human cartilage and correlates with degradation of extracellular matrix during OA progression.

Background: Osteoarthritis (OA) is a debilitating joints disease affecting millions of people worldwide. As OA progresses, chondrocytes experience heightened catabolic activity, often accompanied by alterations in the extracellular environment's osmolarity and acidity. Nevertheless, the precise mechanism by which chondrocytes perceive and respond to acidic stress remains unknown. Recently, there has been growing interest in pH-sensing G protein-coupled receptors (GPCRs), such as GPR68, within musculoskeletal tissues. However, function of GPR68 in cartilage during OA progression remains unknown. This study aims to identify the role of GPR68 in regulation of catabolic gene expression utilizing an in vitro model that simulates catabolic processes in OA. Methods: We examined the expression of GPCR by analyzing high throughput RNA-Seq data in human cartilage isolated from healthy donors and OA patients. De-identified and discarded OA cartilage was obtained from joint arthroplasty and chondrocytes were prepared by enzymatic digestion. Chondrocytes were treated with GPR68 agonist, Ogerin and then stimulated IL1ß and RNA isolation was performed using Trizol method. Reverse transcription was done using the cDNA synthesis kit and the expression of GPR68 and OA related catabolic genes was quantified using SYBR® green assays. Results: The transcriptome analysis revealed that pH sensing GPCR were expressed in human cartilage with a notable increase in the expression of GPR68 in OA cartilage which suggest a potential role for GPR68 in the pathogenesis of OA. Immunohistochemical (IHC) and qPCR analyses in human cartilage representing various stages of OA indicated a progressive increase in GPR68 expression in cartilage associated with higher OA grades, underscoring a correlation between GPR68 expression and the severity of OA. Furthermore, IHC analysis of Gpr68 in murine cartilage subjected to surgically induced OA demonstrated elevated levels of GPR68 in knee cartilage and meniscus. Using IL1ß stimulated in vitro model of OA catabolism, our qPCR analysis unveiled a time-dependent increase in GPR68 expression in response to IL1ß stimulation, which correlates with the expression of matrix degrading proteases suggesting the role of GPR68 in chondrocytes catabolism and matrix degeneration. Using pharmacological activator of GPR68, our results further showed that GPR68 activation repressed the expression of MMPs in human chondrocytes. Conclusions: Our results demonstrated that GPR68 was robustly expressed in human cartilage and mice and its expression correlates with matrix degeneration and severity of OA progression in human and surgical model. GPR68 activation in human chondrocytes further repressed the expression of MMPs under OA pathological condition. These results identify GPR68 as a possible therapeutic target in the regulation of matrix degradation during OA.

Distal Femoral Replacement versus Operative Fixation for Periprosthetic Distal Femur Fractures: A Systematic Review and Meta-Analysis.

BACKGROUND: Open reduction and internal fixation (ORIF) and distal femoral replacement (DFR) have been utilized in the management of periprosthetic distal femur fractures. At present, much of the literature has been limited to small retrospective series. The purpose of the current investigation was to present the results of pooled data to determine the complication rates associated with ORIF and DFR. METHODS: Publications from 2010 to 2020 describing 10 or more periprosthetic distal femur fractures treated with ORIF (ie, single plate, intramedullary nail, and dual fixation) or DFR were included, resulting in 32 publications and 1,258 fractures (977 ORIF and 281 DFR). Occurrence of surgical complications, reoperations, and medical complications were evaluated and compared. RESULTS: The rate of surgical complications (ORIF versus DFR, 20.5 versus 14.9%, P = 1.0) and reoperations (12.9 versus 12.5%, P = 1.0) following DFR were similar. However, pooled analyses demonstrated that patients treated with DFR had a higher medical complication rate (ORIF versus DFR, 8.5 versus 23.1%, P = .0006). CONCLUSION: ORIF and DFR for the treatment of periprosthetic distal femur fractures have similar surgical complication and reoperation profiles. While this review found an increased rate of medical complication following DFR, there are limitations in quality reporting in the literature, which should be considered when interpreting the study's findings. Failed ORIF can be salvaged with DFR, but the difficulty of this reoperation is dependent on the ORIF technique that was used. With future prospective studies, this review can help guide management of these fractures.

Differential chondrogenic differentiation between iPSC derived from healthy and OA cartilage is associated with changes in epigenetic regulation and metabolic transcriptomic signatures.

Induced pluripotent stem cells (iPSCs) are potential cell sources for regenerative medicine. The iPSCs exhibit a preference for lineage differentiation to the donor cell type indicating the existence of memory of origin. Although the intrinsic effect of the donor cell type on differentiation of iPSCs is well recognized, whether disease-specific factors of donor cells influence the differentiation capacity of iPSC remains unknown. Using viral based reprogramming, we demonstrated the generation of iPSCs from chondrocytes isolated from healthy (AC-iPSCs) and osteoarthritis cartilage (OA-iPSCs). These reprogrammed cells acquired markers of pluripotency and differentiated into uncommitted mesenchymal-like progenitors. Interestingly, AC-iPSCs exhibited enhanced chondrogenic potential as compared OA-iPSCs and showed increased expression of chondrogenic genes. Pan-transcriptome analysis showed that chondrocytes derived from AC-iPSCs were enriched in molecular pathways related to energy metabolism and epigenetic regulation, together with distinct expression signature that distinguishes them from OA-iPSCs. Our molecular tracing data demonstrated that dysregulation of epigenetic and metabolic factors seen in OA chondrocytes relative to healthy chondrocytes persisted following iPSC reprogramming and differentiation toward mesenchymal progenitors. Our results suggest that the epigenetic and metabolic memory of disease may predispose OA-iPSCs for their reduced chondrogenic differentiation and thus regulation at epigenetic and metabolic level may be an effective strategy for controlling the chondrogenic potential of iPSCs.

Trunnion Failure in Revision Total Knee Arthroplasty.

In revision total knee arthroplasty, joint kinematics must be maintained amid bone and ligamentous insufficiency. Current modular designs address defects while allowing for intraoperative prosthesis customization through a variety of stem extensions and constraints. Additional constraint improves knee stability while increasing stress at the implant-host interface and modular junction of the implant. This renders the prosthetic stem-condyle junction more prone to fatigue failure. We report 2 cases of prosthetic stem-condyle junction failure in in a varus-valgus constrained revision total knee arthroplasty.

Anterior Revision Hip Arthroplasty is Associated With Higher Wound Complications but Fewer Dislocations Compared to Posterior Revision Hip Surgery.

BACKGROUND: Wound complication after primary direct anterior (DAA) hip arthroplasty has been reported in the literature but there has been no comparison regarding revision anterior vs revision posterior (PA) hip arthroplasty. The authors hypothesize that anterior approach revision surgery may have increased wound complications compared with posterior hip revisions and also report on secondary outcome metrics. METHODS: Ninety-nine DAA and 191 PA revisions were included for analysis. Preoperative demographic characteristics, indication for revision, operative details, type of revision performed, components utilized, and postoperative complications were compared between DAA and PA groups including multivariate analysis. RESULTS: The DAA cohort demonstrated an increased risk of superficial wound complications (7.1% vs 0.5%, P = .003) and a decreased dislocation rate (2.0% vs 13.1%, P = .002). There was a trend toward increased overall complications in the PA group (OR 1.71, P = .078). CONCLUSION: Revision DAA THA is associated with an increased risk of superficial wound complications, but may impart a decreased dislocation rate.

Outcomes of minimally invasive anterolateral THA are not superior to those of minimally invasive direct lateral and posterolateral THA.

BACKGROUND: There has been considerable interest in minimally invasive surgical (MIS) THA in recent years. The MIS anterolateral approach, or the MIS Watson-Jones approach, is a novel intermuscular abductor-sparing technique. Early reports from case series suggest the potential for superior function and reduced complications; however, the available information from clinical reports is inadequate to suggest surgeons should change from their accepted standard approach. QUESTIONS/PURPOSES: We examined the potential superiority of this anterolateral approach, as judged by quality-of-life (QoL) measures, radiographic parameters, and complications, compared to limited-incision MIS direct lateral and MIS posterolateral approaches. METHODS: We performed a prospective randomized controlled trial involving five surgeons at three centers, recruiting 156 patients undergoing primary THA to receive either the MIS anterolateral or the surgeon's preferred approach (direct lateral or posterolateral). For the 135 patients we report, we collected patient-reported WOMAC, SF-36, Paper Adaptive Test in 5 Domains of Quality of Life in Arthritis Questionnaire [PAT5D], and patient satisfaction scores. We recorded complications and evaluated radiographs for prosthetic component position, subsidence, and fracture. Minimum followup was 24 months (mean, 30 months; range, 24-42 months). RESULTS: QoL and patient-reported satisfaction were similar between groups. Radiographic evaluation demonstrated no differences in acetabular component positioning; however, mean stem subsidence was 4.6 mm for the MIS anterolateral group and 4.1 mm for the alternate group, with differences observed among the three centers for stem subsidence and fracture. One center had increased rate of fracture requiring treatment and need for revision in the MIS anterolateral group. CONCLUSIONS: We found no superiority of the MIS anterolateral approach but observed intersite differences in painful stem subsidence and fracture. We have returned to the standard surgical approaches in use before the trial. LEVEL OF EVIDENCE: Level I, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.