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HSS Research Institute
ADULT ORTHOPAEDICS
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HSS Research Institute

Overview
Chief Scientific Officer: Lionel Ivashkiv, MD

Visit the Department Page for the full faculty listing.

The mission of the HSS Research Institute (HSSRI) is to advance the field of musculoskeletal disease research, treatment and prevention and to facilitate the availability of these advancements to our communities so as to extend and improve the lives of our patients.

While the advent of the COVID-19 pandemic and health crisis in March 2020 temporarily limited research at HSS to essential research in the laboratories, many of our scientists initiated COVID-19-related translational research projects, including clinical trials in collaboration with Weill Cornell Medicine. The entire research enterprise began a phased re-opening in May; as of October 2020 we are at 75% onsite capacity while maintaining social distancing and a safe work environment.

During this time we have maintained our productivity, submission of grants and manuscripts, and have initiated strategic planning to further develop and increase impact in our areas of focus in laboratory and clinical research, including identifying opportunities to build interdisciplinary research teams and apply for large center grants.

Below is an overview of our areas of focus and a selection of research highlights within those areas.

Arthritis
UNDERSTANDING RHEUMATOID ARTHRITIS AT THE SINGLE CELL LEVEL
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Laura Donlin, PhD

Laura Donlin, PhD, along with Susan Goodman, MD, Vivien Bykerk, MD, Lionel Ivashkiv, MD, a large team of HSS physicians and scientists, and the NIH-sponsored Accelerating Medicines Partnership (AMP) consortium, used single-cell genomics to define cellular and molecular signatures of cell types present in joint tissues from rheumatoid arthritis (RA) patients.

In a study published in Nature Immunology, they described unique cell populations at high levels in synovial tissue from RA patients. Most significantly, Dr. Donlin and colleagues identified novel subsets of fibroblasts, cells that produce cytokines and destroy joint tissues, and a subset of autoimmune-associated B cells (ABCs) in RA patients. With funding from NIH, Dr. Donlin and colleagues further identified a new pathogenic HBEGF+ macrophage subtype that is enriched in RA joint tissue. These studies, published in Science Translational Medicine, suggest new rational combination therapies for RA as part of a precision medicine approach.

RISK FACTORS FOR POOR ARTHROPLASTY OUTCOMES

Patients with rheumatic diseases such as RA and those with poor socioeconomic status are at risk for failure of total hip and knee replacement. Dr. Goodman and Bella Mehta, MBBS, MS, working with a team of HSS collaborators including surgeons Michael Parks, MD, and Mark Figgie, MD, have shown that patients with rheumatic diseases undergoing arthroplasty are at risk for increased pain and complications such as periprosthetic joint infection (PJI). Using a “big data” approach to assess multiple social determinants of health that affect joint replacement outcomes, they reported in BMC Rheumatology and Arthritis Care and Research that African Americans and other patients from poor neighborhoods, as well as those with less education, have worse arthroplasty outcomes. These patients are more likely to be discharged following surgery to a health care facility or nursing home than Caucasian patients, putting them at higher risk for re-admission.

Excessive scarring (fibrosis) after knee replacement surgery is associated with pain, stiffness, and poor recovery from surgery, and often requires a second (revision) surgery. Applying genomics approaches, Miguel Otero, PhD, worked with a team of HSS collaborators, including Thomas Sculco, MD, Surgeon-in-Chief Emeritus, and orthopaedic surgeon Peter Sculco, MD, to identify dysregulated gene signatures and epigenomic changes in joint tissues from patients who developed postoperative stiffness and fibrosis. These findings were highlighted at the AAOS 2020 Virtual Education Experience, and a manuscript is in preparation. Dr. Otero has also reported in the Journal of Orthopaedic Research that early pro-fibrotic gene expression changes precede the appearance of irreversible structural cartilage damage in preclinical models of OA. These inflammatory and fibrotic changes affect primarily the infrapatellar fat pad (IFP), which is located below the kneecap, and are also present in tissues retrieved from OA patients. Elucidating the mechanisms that lead to the development of fibrosis in OA and in patients after knee replacement surgery is an emerging research area with potential to advance efforts to therapeutically target these processes to prevent disease progression.

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Representative images of Picrosirius Red stains of mouse tissues showing the accumulation of collagen and the development of knee fibrosis in mice loaded for 2 weeks (OA, fibrosis) relative to non-loaded controls.
PHENOTYPING KNEE OSTEOARTHRITIS SUBTYPES USING MACHINE LEARNING

In a study that is currently under way, Drs. Mehta, Goodman and colleagues are prospectively studying patients undergoing knee replacement to define different phenotypes of OA. Prior to surgery, a comprehensive set of data (patient-reported, clinical, socioeconomic, radiographic, and ultrasound) are collected. On the day of surgery, specimens of synovial fluid and tissue, bone, and cartilage are obtained and analyzed by histology, and RNA extracted to examine gene expression. Machine learning approaches are being applied to this “big data” set of information to define categories of osteoarthritis. This comprehensive, state-of-the-art research project will help to identify factors associated with end-stage osteoarthritis of the knee, and will help design individual patient-based management strategies in the future.

Immune Mechanisms in Rheumatic Diseases
Sex Bias in Autoimmune Disease

Systemic lupus erythematosus (SLE) and other autoimmune diseases preferentially affect women. Sex hormones and genes on the X chromosome have been implicated in the heightened susceptibility of women to these disorders. With funding from the National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Department of Defense and the Lupus Research Alliance, Alessandra Pernis, MD, is delineating the molecular networks responsible for lymphocyte dysfunction in SLE pathogenesis. Her lab is building on work published in Nature Immunology and the Journal of Clinical Investigation to explore the pathways that drive expansion of a novel subset of B cells, age/autoimmunity-associated B cells (ABCs), which preferentially expand in females and accumulate prematurely in autoimmune diseases. Dr. Pernis has linked sex differences in a unique lupus model to the function of X-linked gene Tlr7, which encodes immune receptor Toll-like receptor 7 (TLR7). Understanding the roles of ABCs and the sex-bias of SLE will provide the key for novel and more targeted therapies.

Systemic sclerosis (scleroderma), an autoimmune disease characterized by inflammation and thickening of the skin and internal organs, has the highest degree of morbidity and mortality of the rheumatic diseases. Like lupus, scleroderma is three to four times more likely to affect females than males. With funding from NIH National Institute of Allergy and Infectious Diseases and the Scleroderma Foundation, Franck Barrat, PhD, has reported in Science Translational Medicine a pathogenic role for immune receptor Toll-like receptor 8 (TLR8) in scleroderma. He is extending this work to investigate whether aberrant expression of related molecules TLR7 and TLR8 is related to a defect in X chromosome inactivation and contributes to sex skewing of scleroderma.

TARGETING MACROPHAGES TO SUPPRESS INFLAMMATION

Macrophages produce pathogenic inflammatory cytokines that are validated therapeutic targets in inflammatory and autoimmune diseases. Lionel Ivashkiv, MD, published a study in Nature Communications describing how interferon-gamma, a key regulator of immune responses, reprograms macrophages at the epigenomic level to change how these cells respond to environmental challenges.

In another study published in Immunity, Dr. Ivashkiv and HSS colleagues showed a novel role for the master regulator of cholesterol synthesis SREBP in inflammatory responses and wound healing. This work showed unexpected effectiveness of FDA-approved SREBP inhibitors in promoting healing of chronic wounds.

Inez Rogatsky, PhD, has reported in the Journal of Experimental Medicine that in the setting of neuro-inflammation, such as the one seen in multiple sclerosis, the macrophage GRIP1 appears to be permissive for and promoting of disease. This is true despite its being a requirement of the therapeutic actions of type I interferon, typically used to manage MS flares. This work was supported by funding from the NIH National Institute of the Neurological Diseases and Stroke.

IMMUNOPATHOGENESIS AND CLINICAL SEVERITY IN SCLERODERMA

It is unclear which cellular and molecular features underlie clinical improvement in early diffuse cutaneous systemic sclerosis (scleroderma). Kimberly Showalter, MD, and her colleagues Robert Spiera, MD, Jessica Gordon, MD, and Dana Orange, MD, performed histologic/immunophenotypic assessments of skin biopsies in patients with scleroderma who were participating in one of two clinical trials for new treatments. They then applied a machine learning approach using scleroderma gene expression subsets (normal-like, fibroproliferative, inflammatory) as classifiers and skin histology scores as input. They found a gene expression signature in skin fibroblasts that decreases over time only in patients who improved with treatment, but not in non-responders. These findings, published in Annals of the Rheumatic Diseases, may be helpful in identifying useful biomarkers of clinical severity and improvement after treatment in early diffuse scleroderma.

Soft Tissue Repair and Regeneration
PREDICTING POST-OPERATIVE OSTEOARTHRITIS IN THE KNEE

Functioning menisci are critical to knee joint health. If a damaged meniscus cannot be repaired, a section is removed in a partial meniscectomy (PM) procedure. While PM can relieve pain and restore function, the long-term result is an increased predisposition to OA, the development of which is often clinically silent in the early years. Suzanne Maher, PhD, and Scott Rodeo, MD, received a grant from NIH/NIAMS to identify risk factors associated with the development of OA after PM. The study is classifying knee features that can be quantified prior to surgery which are predictive of a high likelihood of early post-operative joint tissue degeneration. Data generated will allow clinicians to identify patients at high risk for post-PM OA for whom modified surgical, pharmacological, and/or rehabilitation techniques could help to mitigate these risk factors.

Harnessing the Immune System to Improve ACL Reconstruction and Tendon Healing

Research over the last decade in Dr. Rodeo’s lab has established the importance of an immune response in healing of tendon to bone that is required for successful rotator cuff repair and anterior cruciate ligament (ACL) reconstruction surgery. More recently Dr. Rodeo has teamed up with Dr. Ivashkiv and Kyung Park-Min, PhD, to apply sophisticated techniques of multiparameter flow cytometry and single cell transcriptomics to gain insight into the immune response after surgery and how it can be therapeutically modulated. This NIH-supported work has revealed two subtypes of macrophages that have opposing effects on wound healing, including a novel “surgery-induced” macrophage population that appears within a day of surgery, is highly inflammatory, and likely deleterious for healing. In contrast, a population of regenerative macrophages increasingly infiltrates the surgical site beginning a week after surgery. The research team is testing therapeutic approaches to modulate the balance between these macrophage subtypes to improve healing and surgical outcomes.

Bone Health
UNDERSTANDING MECHANISMS FOR BUILDING BONE TISSUE

While surgical and engineering strategies have been devised to improve joint replacement outcomes, mechanical loosening (the failure of implants to integrate with bone tissue) remains a clinical challenge. Ugur Ayturk, PhD, is applying advanced genomic technologies and mouse joint implantation models to define the biologic mechanisms of integration following surgical insertion of orthopaedic devices into bone. Using a mouse model, Dr. Ayturk and colleagues identified a population of osteoprogenitor cells (PαS skeletal stem cells) in the bone marrow that potentially could be manipulated to increase bone formation and improve implant fixation.

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(Left) Fluorescently labelled osteoblasts form bone around a titanium implant in mouse tibia. (Right) Fluorescently labelled cells give rise to osteocytes in peri-implant bone tissue.

This work is under revision at the leading journal in the bone field, the Journal of Bone and Mineral Research. In collaboration with Mathias Bostrom, MD, and Xu Yang, MD, Dr. Ayturk is characterizing the biologic mechanisms that activate PαS cells towards osteogenesis and will determine if these cells can be induced to enhance osseointegration. These studies will provide a deeper understanding of how osteoblasts, bone-forming cells, arise from precursor cells to build new bone tissue, and suggest novel strategies to improve implant fixation.

ERADICATING ORTHOPAEDIC JOINT INFECTIONS

Among the most devasting complications that can result from orthopaedic surgery is periprosthetic joint infection (PJI), in which an infection develops around the site of the artificial joint. A team of surgeons, immunologists, and infectious disease specialists has joined forces at HSS to improve diagnosis and treatment of PJI.

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Biofilm formation on a mouse model fitted with a 3-D printed Ti-6Al-4V implant capable of bearing weight and permitting quantitative analysis of PJI load.

The research on PJI diagnosis is using next generation sequencing technologies to detect pathogenic microbe-derived DNA in the blood, offering the promise of a blood test for diagnosing and monitoring response to therapy noninvasively. This work has been submitted for publication and commercialization is being developed with a partner from industry.

Taking Aim at Prosthetic Joint Infections
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Predicting Rheumatoid Arthritis Flares
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