Welcome to Zuscik Lab

Lab Director, Michael Zuscik, PhD

Welcome to Zuscik Lab

Michael Zuscik, PhD

Michael Zuscik, PhD

Mack Clayton Professor
Vice Chair of Research

Advancing Orthopedic Research: Exploring Obesity Impact, Microbiome Role, and Disease-Modifying Treatments"

The central focus of our research can be divided programmatically into three parts:  1) Study of the pathological impact of obesity on the skeleton, particularly bone and joint health and fracture healing, 2) Elucidating the role of the gut microbiome in posttraumatic and obesity-associated osteoarthritis, and 3) Development of disease-modifying treatments to address joint degeneration in osteoarthritis.  Our work spans from bench to bedside, involving basic molecular-cellular biology and microbiology in microbial and cell culture systems, state-of-the-art animal models of disease, and human clinical trials.  Our aim is to pursue a basic study of skeletal homeostasis and disease, using information gained from that work to develop therapeutic strategies addressing key orthopedic challenges including fracture non-union, osteoporosis, and osteoarthritis.

 


Projects

 

Impact of obesity on the skeleton

Impact of obesity on the skeleton: Key discoveries made by our group have documented the pathological impact of obesity on the musculoskeletal system. We have begun to understand the tissue and molecular basis underlying accelerated OA, delayed bone healing, and reduced skeletal bone mass in the obese context. We have documented that insulin resistance and chronic inflammation are key mechanisms of pathogenesis, and we have now discovered that dysbiosis of the gut microbiome in obesity may be a key root cause of these orthopedic problems. Identification of the tissue and molecular mechanisms in each of these situations has energized the assembly of a programmatic team of investigators that work collaboratively to unravel the novel idea that gut microbiome-skeletal interactions are important in homeostasis and disease.

View All Projects

Publications

  • GWAS-Informed data integration and non-coding CRISPRi screen illuminate genetic etiology of bone mineral density

    Pub Date: 4/2/2024
    Journal: bioRxiv [Preprint]. 2024 Dec 29:2024.03.19.585778.
    Authors: Mitchell Conery James A Pippin Yadav Wagley Khanh Trang Matthew C Pahl David A Villani Lacey J Favazzo Cheryl L Ackert-Bicknell Michael J Zuscik Eugene Katsevich Andrew D Wells Babette S Zemel Benjamin F Voight Kurt D Hankenson Alessandra Chesi Struan F A Grant
    PMID: 38562830
    PMCID: PMC10983984
    Over 1,100 independent signals have been identified with genome-wide association studies (GWAS) for bone mineral density (BMD), a key risk factor for mortality-increasing fragility fractures; however, the effector gene(s) for most remain unknown. Informed by a variant-to-gene mapping strategy implicating 89 non-coding elements predicted to regulate osteoblast gene expression at BMD GWAS loci, we executed a single-cell CRISPRi screen in human fetal osteoblasts (hFOBs). The BMD relevance of hFOBs...

  • Understanding the Transcriptomic Landscape to Drive New Innovations in Musculoskeletal Regenerative Medicine

    Pub Date: 2/14/2022
    Journal: Curr Osteoporos Rep. 2022 Apr;20(2):141-152.
    Authors: Stacey M Thomas Cheryl L Ackert-Bicknell Michael J Zuscik Karin A Payne
    PMID: 35156183
    PURPOSE OF REVIEW: RNA-sequencing (RNA-seq) is a novel and highly sought-after tool in the field of musculoskeletal regenerative medicine. The technology is being used to better understand pathological processes, as well as elucidate mechanisms governing development and regeneration. It has allowed in-depth characterization of stem cell populations and discovery of molecular mechanisms that regulate stem cell development, maintenance, and differentiation in a way that was not possible with...

  • A White Paper on Collagen Hydrolyzates and Ultrahydrolyzates: Potential Supplements to Support Joint Health in Osteoarthritis?

    Pub Date: 10/30/2021
    Journal: Curr Rheumatol Rep. 2021 Oct 30;23(11):78.
    Authors: Ali Mobasheri Armaghan Mahmoudian Ursule Kalvaityte Ilona Uzieliene Christina E Larder Michèle M Iskandar Stan Kubow Paulo Cesar Hamdan Cyro Scala de Almeida Lacey J Favazzo Luc J C van Loon Pieter J Emans Pérola G Plapler Michael J Zuscik
    PMID: 34716494
    PMCID: PMC8556166
    PURPOSE OF REVIEW: Osteoarthritis (OA) is the most common forms of arthritis in the general population, accounting for more pain and functional disability than any other musculoskeletal disease. There are currently no approved disease modifying drugs for OA. In the absence of effective pharmacotherapy, many patients with OA turn to nutritional supplements and nutraceuticals, including collagen derivatives. Collagen hydrolyzates and ultrahydrolyzates are terms used to describe collagens that have...

  • IKKβ-NF-κB signaling in adult chondrocytes promotes the onset of age-related osteoarthritis in mice

    Pub Date: 9/21/2021
    Journal: Sci Signal. 2021 Sep 21;14(701):eabf3535.
    Authors: Sarah E Catheline Richard D Bell Luke S Oluoch M Nick James Katherine Escalera-Rivera Robert D Maynard Martin E Chang Christopher Dean Elizabeth Botto John P Ketz Brendan F Boyce Michael J Zuscik Jennifer H Jonason
    PMID: 34546791
    PMCID: PMC8734558
    Canonical nuclear factor κB (NF-κB) signaling mediated by homo- and heterodimers of the NF-κB subunits p65 (RELA) and p50 (NFKB1) is associated with age-related pathologies and with disease progression in posttraumatic models of osteoarthritis (OA). Here, we established that NF-κB signaling in articular chondrocytes increased with age, concomitant with the onset of spontaneous OA in wild-type mice. Chondrocyte-specific expression of a constitutively active form of inhibitor of κB kinase β (IKKβ)...

  • Paroxetine-mediated GRK2 inhibition is a disease-modifying treatment for osteoarthritis

    Pub Date: 2/11/2021
    Journal: Sci Transl Med. 2021 Feb 10;13(580):eaau8491.
    Authors: Elijah L Carlson Vengadeshprabhu Karuppagounder William J Pinamont Natalie K Yoshioka Adeel Ahmad Eric M Schott Heather K Le Bleu Michael J Zuscik Reyad A Elbarbary Fadia Kamal
    PMID: 33568523
    Osteoarthritis (OA) is a debilitating joint disease characterized by progressive cartilage degeneration, with no available disease-modifying therapy. OA is driven by pathological chondrocyte hypertrophy (CH), the cellular regulators of which are unknown. We have recently reported the therapeutic efficacy of G protein-coupled receptor kinase 2 (GRK2) inhibition in other diseases by recovering protective G protein-coupled receptor (GPCR) signaling. However, the role of GPCR-GRK2 pathway in OA is...


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