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Excess Growth Hormone Triggers Inflammation-Associated Arthropathy, Subchondral Bone Loss, and Arthralgia

Poudel, Sher Bahadur; Ruff, Ryan R; Yildirim, Gozde; Dixit, Manisha; Michot, Benoit; Gibbs, Jennifer L; Ortiz, Silvana Duran; Kopchick, John J; Kirsch, Thorsten; Yakar, Shoshana
Growth hormone (GH) is a key mediator of skeletal growth. In humans, excess GH secretion due to pituitary adenoma, seen in patients with acromegaly, results in severe arthropathies. This study investigated the effects of long-term excess GH on the knee joint tissues. One year-old wild-type (WT) and bovine GH (bGH) transgenic mice were used as a model for excess GH. bGH mice showed increased sensitivity to mechanical and thermal stimuli, compared with WT mice. Micro-computed tomography analyses of the distal femur subchondral bone revealed significant reductions in trabecular thickness and significantly reduced bone mineral density of the tibial subchondral bone-plate that were associated with increased osteoclast activity in both male and female bGH compared with WT mice. bGH mice showed severe loss of matrix from the articular cartilage, osteophytosis, synovitis, and ectopic chondrogenesis. Articular cartilage loss in the bGH mice was associated with elevated markers of inflammation and chondrocyte hypertrophy. Finally, hyperplasia of synovial cells was associated with increased expression of Ki-67 and diminished p53 levels in the synovium of bGH mice. Unlike the low-grade inflammation seen in primary osteoarthritis, arthropathy caused by excess GH affects all joint tissues and triggers severe inflammatory response. Data of this study suggest that treatment of acromegalic arthropathy should involve inhibition of ectopic chondrogenesis and chondrocyte hypertrophy.
PMID: 36870529
ISSN: 1525-2191
CID: 5435002

In vivo multimodal imaging of hyaluronan-mediated inflammatory response in articular cartilage

Ruiz, Amparo; Duarte, Alejandra; Bravo, Dalibel; Ramos, Elisa; Zhang, Chongda; Cowman, Mary K; Kirsch, Thorsten; Milne, Mark; Luyt, Leonard G; Raya, José G
OBJECTIVE:One driving factor in the progression to posttraumatic osteoarthritis (PTOA) is the perpetuation of the inflammatory response to injury into chronic inflammation. Molecular imaging offers many opportunities to complement the sensitivity of current imaging modalities with molecular specificity. The goal of this study was to develop and characterize agents to image hyaluronan (HA)-mediated inflammatory signaling. DESIGN/METHODS:We developed optical (Cy5.5-P15-1) and magnetic resonance contrast agents (Gd-DOTA-P15-1) based in a hyaluronan-binding peptide (P15-1) that has shown anti-inflammatory effects on human chondrocytes, and validated them in vitro and in vivo in two animal models of PTOA. RESULTS:In vitro studies with a near infrared (NIR) Cy5.5-P15-1 imaging agent showed a fast and stable localization of Cy5.5-P15-1 on chondrocytes, but not in synovial cells. In vivo NIR showed significantly higher retention of imaging agent in PTOA knees between 12 and 72h (n=8, Cohen's d>2 after 24h). NIR fluorescence accumulation correlated with histologic severity in cartilage and meniscus (ρ between 0.37 and 0.57, p<0.001). By using in vivo magnetic resonance imaging with a Gd-DOTA-P15-1 contrast agent in 12 rats, we detected a significant decrease of T1 on injured knees in all cartilage plates at 48h (-15%, 95%-confidence interval (CI)=[-18%,-11%] []) while no change was observed in the controls (-2%, 95%-CI=[-5%,+1%]). CONCLUSIONS:This study provides the first in vivo evidence that hyaluronan-related inflammatory response in cartilage after injury is a common finding. Beyond P15-1, we have demonstrated that molecular imaging can provide a versatile technology to investigate and phenotype PTOA pathogenesis, as well as study therapeutic interventions.
PMID: 34774790
ISSN: 1522-9653
CID: 5048842

Sexual dimorphic impact of adult-onset somatopause on life span and age-induced osteoarthritis

Poudel, Sher Bahadur; Dixit, Manisha; Yildirim, Gozde; Cordoba-Chacon, Jose; Gahete, Manuel D; Yuji, Ikeno; Kirsch, Thorsten; Kineman, Rhonda D; Yakar, Shoshana
Osteoarthritis (OA), the most prevalent joint disease, is a major cause of disability worldwide. Growth hormone (GH) has been suggested to play significant roles in maintaining articular chondrocyte function and ultimately articular cartilage (AC) homeostasis. In humans, the age-associated decline in GH levels was hypothesized to play a role in the etiology of OA. We studied the impact of adult-onset isolated GH deficiency (AOiGHD) on the life span and skeletal integrity including the AC, in 23- to 30-month-old male and female mice on C57/BL6 genetic background. Reductions in GH during adulthood were associated with extended life span and reductions in body temperature in female mice only. However, end-of-life pathology revealed high levels of lymphomas in both sexes, independent of GH status. Skeletal characterization revealed increases in OA severity in AOiGHD mice, evidenced by AC degradation in both femur and tibia, and significantly increased osteophyte formation in AOiGHD females. AOiGHD males showed significant increases in the thickness of the synovial lining cell layer that was associated with increased markers of inflammation (IL-6, iNOS). Furthermore, male AOiGHD showed significant increases in matrix metalloproteinase-13 (MMP-13), p16, and β-galactosidase immunoreactivity in the AC as compared to controls, indicating increased cell senescence. In conclusion, while the life span of AOiGHD females increased, their health span was compromised by high-grade lymphomas and the development of severe OA. In contrast, AOiGHD males, which did not show extended life span, showed an overall low grade of lymphomas but exhibited significantly decreased health span, evidenced by increased OA severity.
PMID: 34240807
ISSN: 1474-9726
CID: 4933602

Protective Effects of a Hyaluronan-Binding Peptide (P15-1) on Mesenchymal Stem Cells in an Inflammatory Environment

Kirsch, Thorsten; Zhang, Fenglin; Braender-Carr, Olivia; Cowman, Mary K
Mesenchymal stem cells (MSCs) obtained from various sources, including bone marrow, have been proposed as a therapeutic strategy for the improvement of tissue repair/regeneration, including the repair of cartilage defects or lesions. Often the highly inflammatory environment after injury or during diseases, however, greatly diminishes the therapeutic and reparative effectiveness of MSCs. Therefore, the identification of novel factors that can protect MSCs against an inflammatory environment may enhance the effectiveness of these cells in repairing tissues, such as articular cartilage. In this study, we investigated whether a peptide (P15-1) that binds to hyaluronan (HA), a major component of the extracellular matrix of cartilage, protects bone-marrow-derived MSCs (BMSCs) in an inflammatory environment. The results showed that P15-1 reduced the mRNA levels of catabolic and inflammatory markers in interleukin-1beta (IL-1β)-treated human BMSCs. In addition, P15-1 enhanced the attachment of BMSCs to HA-coated tissue culture dishes and stimulated the chondrogenic differentiation of the multipotential murine C3H/10T1/2 MSC line in a micromass culture. In conclusion, our findings suggest that P15-1 may increase the capacity of BMSCs to repair cartilage via the protection of these cells in an inflammatory environment and the stimulation of their attachment to an HA-containing matrix and chondrogenic differentiation.
PMID: 34209086
ISSN: 1422-0067
CID: 4927092

COVID-19 and pm exposure: Identifying and mitigating the synergistic deleterious effects [Meeting Abstract]

Young, I R; Cowman, M K; Kirsch, T; Crowley, G; Nolan, A
RATIONALE Coronavirus Disease-2019(COVID-19), caused by the severe acute respiratory syndrome coronavirus-2(SARS-CoV-2), causes multi-organ failure and death. Metabolic syndrome(MetSyn) characteristics are also risks for COVID-19. The Receptor for Advanced Glycation End-Products(RAGE) is a MetSyn mediator. SARS-CoV via its Spike protein binds ACE2 as its 1o-receptor, and may activate TLR2. Particulate matter(PM) similarly activates an innate immune response, partially via the RAGE receptor, and increases ACE2 expression. Excessive hyaluronan(HA) levels are found in lungs of COVID-19 patients. Reducing HA synthesis and stabilizing the HA shield surrounding cells may be therapeutic. A HA-binding peptide, P15-1, is anti-inflammatory and reduces HA. HA and its binding proteins may provide a link explaining synergistic ACE2 and RAGE signaling, reducing interaction of receptors with their ligands and ultimately inflammation-related changes in peripheral blood mononuclear cells(PBMCs), the severity of which correlate with patient outcome after SARS-CoV-2 exposure. Our focus is to develop novel therapeutic strategies for SARS-CoV-2 inflammation. To begin to explore our HYPOTHESIS that COVID-19 Spike protein and PM co-exposure synergistically induces an inflammatory phenotype and that phenotype can be mitigated by stabilizing the pericellular HA matrix and by inhibiting RAGE. METHODS. We performed in vitro exposure of PBMCs isolated from 9/11 World Trade Center(WTC) 1st- Responders to i. Media alone(MA); ii. WTC PM; iii. SARS-CoV-2 Spike RBD(C19); iv. C19 and PM; v. C19 and P15-1; vi. C19, PM and P15-1 vii. C19, PM and RAGE inhibitor(RAGEInh) FPS-ZM1; viii. LPS(positive control). Total mRNA levels for Cox-2, IL-1beta, IL-6 and MMP-13 24 hours after exposure were analyzed by real time PCR. Comparisons by Student's t- and Mann-Whitney U-tests. Correlations by Spearman's. Significance p<0.05. RESULTS COX-2, IL-1beta, IL-6 and MMP-13 mRNA levels were significantly increased 24-hrs after the administration of PM and C19. Co-exposure to PM and C19 yielded a synergistic increase in the mRNA of IL-beta, Figure 1B. P15-1 and RAGE inhibition significantly reduced mRNA levels of inflammatory markers in primary PBMCs exposed to C19, WTC PM, or a combination of the two, Figure 1. CONCLUSIONS Our work focuses on mitigating the COVID-19 inflammatory phenotype by stabilizing the pericellular HA matrix and by inhibiting RAGE. Preliminary data presented in this abstract will be further explored using PBMCs and cell lines in a multidisciplinary approach
EMBASE:635307981
ISSN: 1535-4970
CID: 4915652

IN VIVO MULTIMODAL IMAGING OF INFLAMMATION IN ARTICULAR CARTILAGE AFTER JOINT INJURY [Meeting Abstract]

Ruiz, A.; Duarte, A.; Bravo, D.; Ramos, E.; Zhang, C.; Koch, R.; Cowman, M. K.; Kirsch, T.; Milne, M.; Luyt, L. G.; Raya, J. G.
ISI:000642588500432
ISSN: 1063-4584
CID: 4892922

Use of a Modified Rep Model in Primary Joint Arthroplasty: Lessons Learned

Meftah, Morteza; Siddappa, Vinay Hosuru; Johnson, Nathan; White, Peter B; Mack, Arthur; Skoller, Michael; Kirschenbaum, Ira H
Orthopedic implant device sales representatives ("reps") can provide intraoperative guidance based on their product knowledge, as part of their many responsibilities. However, for experienced high-volume arthroplasty surgeons, a representative may not be required in the room for most primary total knee arthroplasty (TKA) procedures. The goal of this study was to describe the authors' experience with a modified rep model for primary TKA. Between January and December 2017, a total of 100 unilateral primary TKAs were performed with a modified rep model and compared with 100 primary TKAs that were performed before this protocol. The authors adopted 2 additional initiatives to institute this protocol safely: (1) improved education of operating room staff and allocation of responsibilities; and (2) reengineering of the existing surgical trays. No perioperative complications, including readmission, periprosthetic fracture, or infection, occurred in either group. In addition, no difference was found in mean length of stay between the modified rep and conventional cohorts (2.2 and 2.4 days, respectively; P=.49). Mean operating room time was less with the modified rep cohort (102.1 vs 117.8 minutes; P<.001), as was total instrument turnover time in the operating room (13.9 vs 29.7 minutes; P<.0001) and in central sterilization (59.4 vs 126.8 minutes; P<.001). No errors occurred with implant accuracy or trays, and there was no need to change the type of implant with the modified rep model, compared with 6% of trays requiring additional sterilization with the conventional model. The negotiated implant cost with the modified rep model was approximately $2000 less than that for the conventional group. This study found that the modified rep model for primary TKA is safe and has the potential for substantial cost savings. [Orthopedics. 202x;4x(x):xx-xx.].
PMID: 32882047
ISSN: 1938-2367
CID: 4588472

Extracellular vesicles released from articular chondrocytes play a major role in cell-cell communication

Liu, Xiaoming; Shortt, Claire; Zhang, Fenglin; Bater, Mariah Q; Cowman, Mary K; Kirsch, Thorsten
The purpose of this investigation was to determine the role of extracellular vesicles (EVs), released from articular chondrocytes in a physiological or pathological state, in cell-cell communication with other articular chondrocytes or chondrocytic precursor cells. Conditioned medium from interleukin-1beta (IL-1β)-treated human articular chondrocytes stimulated catabolic events and inhibited type II collagen expression in articular chondrocytes to a much greater degree than medium from IL-1β-treated chondrocytes after complete removal of EVs. Vehicle-treated and IL-1β-treated human articular chondrocytes released EVs of similar size; however the number of EVs released by IL-1β-treated chondrocytes was markedly higher than the number of EVs released from vehicle-treated cells. Furthermore, our findings demonstrate that similar to medium from IL-1β-treated chondrocytes containing EVs, EVs isolated from medium of IL-1β-treated chondrocytes stimulated catabolic events in articular chondrocytes, whereas EVs isolated from the medium of vehicle-treated chondrocytes inhibited catabolic events and increased mRNA levels of aggrecan and type II collagen in IL-1β-treated chondrocytes. Furthermore, medium containing EVs from vehicle-treated articular chondrocytes or EVs isolated from this medium stimulated chondrogenesis of C3H10T1/2 cells, whereas medium containing EVs from IL-1β-treated chondrocytes or EVs isolated from this medium inhibited chondrogenesis. Our findings suggest that EVs released by articular chondrocytes play a key role in the communication between joint cells and ultimately in joint homeostasis, maintenance, pathology, and repair. This article is protected by copyright. All rights reserved.
PMID: 31736104
ISSN: 1554-527x
CID: 4208482

A Hyaluronan-binding Peptide (P15-1) Reduces Inflammatory and Catabolic Events in IL-1β-treated Human Articular Chondrocytes

Shortt, Claire; Luyt, Leonard G; Turley, Eva A; Cowman, Mary K; Kirsch, Thorsten
Inflammation plays a critical role in osteoarthritis (OA). It stimulates catabolic events in articular chondrocytes and prevents chondrogenic precursor cells from repairing cartilage lesions, leading to accelerated cartilage degradation. Therefore, the identification of novel factors that reduce catabolic events in chondrocytes and enhances chondrogenic differentiation of precursor cells in an inflammatory environment may provide novel therapeutic strategies for the treatment of OA. The goal of this study was to determine whether a hyaluronan (HA)-binding peptide (P15-1), via interacting with high molecular weight (HMW)HA can enhance the anti-inflammatory properties of HMWHA and decrease catabolic events in interleukin-1beta (IL-1β)-treated human articular chondrocytes. Treatment with P15-1 decreased catabolic events and stimulated anabolic events in articular chondrocytes cultured in an inflammatory environment. P15-1 pre-mixed with HMWHA was more effective in inhibiting catabolic events and stimulating anabolic events than P15-1 or HMWHA alone. Our findings suggest that P15-1 together with HMWHA inhibits catabolic events in articular chondrocytes via the inhibition of p38 mitogen-activated protein kinases (MAPK) and increasing the thickness of the pericellular matrix (PCM) around chondrocytes thereby decreasing catabolic signaling. Finally, conditioned medium from IL-1β and P15-1-treated human articular chondrocytes was less inhibitory for chondrogenic differentiation of precursor cells than conditioned medium from chondrocytes treated with IL-1β alone. In conclusion, P15-1 is proposed to function synergistically with HMWHA to enhance the protective microenvironment for chondrocytes and mesenchymal stem cells during inflammation and regeneration.
PMID: 31996703
ISSN: 2045-2322
CID: 4294272

Efficacy of Adductor Canal Block With Liposomal Bupivacaine: A Randomized Prospective Clinical Trial

Meftah, Morteza; Boenerjous-Abel, Suhas; Siddappa, Vinay H; Kirschenbaum, Ira H
This study compared the postoperative analgesic efficacy of liposomal bupivacaine as a single-administration adductor canal block (ACB) vs periarticular injection (PAI) for pain control after total knee arthroplasty (TKA). From May 2016 to June 2017, a total of 70 unilateral TKA patients were randomized into 2 groups: PAI (extended-release bupivacaine 266 mg [20-mL vial] with 20 mL of 0.5% bupivacaine hydrochloride and normal saline to a total volume of 120 mL) and ACB (subsartorial saphenous nerve using extended-release bupivacaine 266 mg [20-mL vial]). All patents underwent spinal anesthesia with comprehensive preemptive and postoperative multi-modal pain protocol. All opioids administered were converted to morphine equivalents. Pain was recorded at 4 to 12 hours on the day of surgery, and on postoperative days 1, 2, and 3. Patients and investigators other than the surgeon and anesthesiologist were blinded to the study. The difference in pain scores between the PAI and ACB groups was not statistically significant during the first 12 hours (day 0) after surgery or on postoperative day 1 (5.31 vs 4.26, P=.091). However, on postoperative day 3, the mean pain score increased in the ACB group and decreased in the PAI group (4.8 vs 1.83, P=.037). There was no statistically significant difference between the 2 groups regarding the accumulative daily converted morphine equivalent consumption or total consumption. Although the PAI group demonstrated longer lasting pain relief than the ACB group for the duration of the study, other outcomes were similar between the 2 groups. [Orthopedics. 202x; xx(x):xx-xx.].
PMID: 31770446
ISSN: 1938-2367
CID: 4237762