Lab Research Projects

Oxidative stress and the development of osteoarthritis:

The long-term objective of this project is to determine the fundamental mechanisms by which oxidative stress conditions contribute to the pathogenesis of osteoarthritis (OA), with a focus on age-related OA. Cell senescence is a major factor contributing to age-related diseases, including OA. A central mechanism is the production of inflammatory cytokines and matrix degrading enzymes by senescent cells, referred to as the senescence-associated secretory phenotype (SASP). The goal of this project is to understand the mechanisms by which oxidative stress governs development and maintenance of the SASP in the joint.

Diekman BO, Loeser RF. Aging and the emerging role of cellular senescence in osteoarthritis. Osteoarthritis and Cartilage 2024; 32: 365-371.

Collins JA, Kim CJ, Coleman A, Little A, Perez MM, Clarke EJ, Diekman B, Peffers MJ, Chubinskaya S, Tomlinson RE, Freeman TA, Loeser RF. Cartilage-specific Sirt6 deficiency represses IGF-1 and enhances osteoarthritis severity in mice. Ann Rheum Dis. 2023; 82:1464-1473.

Taylor EL, Collins JA, Gopalakrishnan P, Chubinskaya S, Loeser RF. Age and oxidative stress regulate Nrf2 homeostasis in human articular chondrocytes. Osteoarthritis Cartilage 2023; 31:1214-1223.

Integrin signaling in osteoarthritis:

The long-term goal of this project is to determine the basic mechanisms by which signals generated through the α5β1 integrin receptor contribute to the progression of osteoarthritis (OA). We are defining the mechanism by which α5β1 integrin signals generated by the matrikine FN7-10 promote expression of proinflammatory and matrix degrading genes by chondrocytes, synovial fibroblasts, and other joint resident cells that contribute to OA. We are also determining the mechanism by which activation of α5β1 signaling drives OA phenotypes in vivo using a novel transgenic mouse that expresses FN7-10.

Miao MZ, Lee, JS, Yamada KM, Loeser RF. Integrin signaling in joint development, homeostasis and osteoarthritis. Nat Rev Rheumatol 2024; 20:492-509.

Miao MZ, Su QP, Cui Y, Bahnson EM, Li G, Wang M, Yang Y, Collins JA, Wu Di, Gu Q, Chubinskaya S, Diekman BO, Yamada KM, Loeser RF. Redox-active endosomes mediate α5β1 integrin signaling and promote chondrocyte matrix metalloproteinase production in osteoarthritis. Science Signaling 2023; 16:82-99.

Drug discovery for osteoarthritis:

The overall goal of this project is to use a recently developed, novel, high throughput small molecule screening technology combined with target prioritization tools and testing in preclinical models to identify signaling pathways and therapeutic targets for prevention or mitigation of OA. Our overall hypothesis is that small molecules that target specific disease pathways that regulate expression of multiple OA mediators and that are activated by joint injury will prevent the development of structural damage that leads to OA.

Coryell PR, Hardy PB, Chubinskaya S, Pearce KH, Loeser RF. A novel small molecule screening assay using normal human chondrocytes toward osteoarthritis drug discovery. PLoS ONE 2024; 19(11): e0308647.

Identifying novel osteoarthritis risk genes using GWAS, chondrocyte genomics, and genome editing:

This is a collaborative project with the Phanstiel and Diekman labs. The overall objective is to identify putative causal knee OA risk variants, map them to their target genes, and quantify their phenotypic impact in chondrocytes. This project has been expanded to identify potential OA risk variants in synovial fibroblasts.

Byun S, Shine J., Coryell P, Kramer NE, D’Costa S., Thulson E, Parkus SM, Chubinskaya S, Loeser RF*, Diekman BO*, Phanstiel DH*. Response splicing quantitative trait loci in primary human chondrocytes identify putative osteoarthritis risk genes. Nature Communications 2025; 16 (1) :7932.

Kramer NE, Byun S, Coryell P, D’Costa S, Thulson E, Kim H, Parkus SM, Bond ML, Klein ER, Shine J, Chubinskaya S, Love MI, Mohlke KL, Diekman BO*, Loeser RF*, Phanstiel, DH*. Response eQTLs, chromatin accessibility, and 3D chromatin structure in chondrocytes provide mechanistic insight into osteoarthritis risk. Cell Genomics 2025; 5: 100738.