Projects

Ongoing Projects

FOXO TRANSCRIPTION FACTORS IN JOINT AGING AND OSTEOARTHRITIS PATHOGENESIS
This study examines the role of FoxO transcription factors in regulating mechanisms of joint homeostasis and consequences of reduced FoxO expression in cartilage for joint aging and osteoarthritis pathogenesis. Experimental approaches to increase FoxO will be tested for therapeutic potential in experimental osteoarthritis.

Funding
NIH/NIA R37 AG059418 04/01/18-03/31/28
ROLE: Lotz (PI)

Publications
Targeting FoxO transcription factors with HDAC inhibitors for the treatment of osteoarthritis.
Ohzono H, Hu Y, Nagira K, Kanaya H, Okubo N, Olmer M, Gotoh M, Kurakazu I, Akasaki Y, Kawata M, Chen E, Chu AC, Johnson KA, Lotz MK.
Ann Rheum Dis. 2022 Sep 15:annrheumdis-2021-221269. doi: 10.1136/ard-2021-221269. Online ahead of print. PMID: 36109140

Genome-Wide Occupancy Profiling Reveals Critical Roles of FoxO1 in Regulating Extracellular Matrix and Circadian Rhythm Genes in Human Chondrocytes.
Duffy T, Bekki H, Lotz MK.
Arthritis Rheumatol. 2020 Sep;72(9):1514-1523. doi: 10.1002/art.41284. Epub 2020 Aug 9. PMID: 32281255

FOXO1 and FOXO3 transcription factors have unique functions in meniscus development and homeostasis during aging and osteoarthritis.
Lee KI, Choi S, Matsuzaki T, Alvarez-Garcia O, Olmer M, Grogan SP, D'Lima DD, Lotz MK.
Proc Natl Acad Sci U S A. 2020 Feb 11;117(6):3135-3143. doi: 10.1073/pnas.1918673117. Epub 2020 Jan 24. PMID: 31980519

FOXO1 transcription factor regulates chondrogenic differentiation through transforming growth factor β1 signaling.
Kurakazu I, Akasaki Y, Hayashida M, Tsushima H, Goto N, Sueishi T, Toya M, Kuwahara M, Okazaki K, Duffy T, Lotz MK, Nakashima Y.
J Biol Chem. 2019 Nov 15;294(46):17555-17569. doi: 10.1074/jbc.RA119.009409. Epub 2019 Oct 10. PMID: 31601652

Identification of transcription factors responsible for dysregulated networks in human osteoarthritis cartilage by global gene expression analysis.
Fisch KM, Gamini R, Alvarez-Garcia O, Akagi R, Saito M, Muramatsu Y, Sasho T, Koziol JA, Su AI, Lotz MK.
Osteoarthritis Cartilage. 2018 Nov;26(11):1531-1538. doi: 10.1016/j.joca.2018.07.012. Epub 2018 Aug 3. PMID: 30081074

FoxO transcription factors modulate autophagy and proteoglycan 4 in cartilage homeostasis and osteoarthritis.
Matsuzaki T, Alvarez-Garcia O, Mokuda S, Nagira K, Olmer M, Gamini R, Miyata K, Akasaki Y, Su AI, Asahara H, Lotz MK.
Sci Transl Med. 2018 Feb 14;10(428):eaan0746. doi: 10.1126/scitranslmed.aan0746. PMID: 29444976

FoxO transcription factors support oxidative stress resistance in human chondrocytes.
Akasaki Y, Alvarez-Garcia O, Saito M, Caramés B, Iwamoto Y, Lotz MK.
Arthritis Rheumatol. 2014 Dec;66(12):3349-58. doi: 10.1002/art.38868. PMID: 25186470

Dysregulated FOXO transcription factors in articular cartilage in aging and osteoarthritis.
Akasaki Y, AHasegawa A, Saito M, Asahara H, Iwamoto Y, Lotz MK.
Osteoarthritis Cartilage. 2014 Jan;22(1):162-70. doi: 10.1016/j.joca.2013.11.004. Epub 2013 Nov 21 PMID: 24269635

KLF4 TRANSCRIPTION FACTORS IN JOINT DEGRADATION AND REGENERATION
The goal of this project is to determine the role of KLF4 in cartilage homeostasis and the consequences of KLF4 suppression for joint aging and OA pathogenesis. We will also establish proof of concept for KLF4 as a therapeutic target in OA.

Funding
NIH/NIA R01 AG056144 09/01/18-05/31/23
ROLE: Lotz PI

Publications
Krüppel-like factor-4 and Krüppel-like factor-2 are important regulators of joint tissue cells and protect against tissue destruction and inflammation in osteoarthritis.
Kawata M, Teramura T, Ordoukhanian P, Head SR, Natarajan P, Sundaresan A, Olmer M, Asahara H, Lotz MK.
Ann Rheum Dis. 2022 May 9:annrheumdis-2021-221867. doi: 10.1136/annrheumdis-2021-221867. Online ahead of print. PMID: 35534137

Mocetinostat activates Krüppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis.Kawata M, McClatchy DB, Diedrich JK, Olmer M, Johnson KA,Yates JR, Lotz MK. JCI Insight. 2023 Sep 8:8(17)e170513. doi: 10.1172/jci.insight.17053.

INTEGRATIVE OMICS ANALYSIS OF HUMAN CARTILAGE IN AGING AND OSTEOARTHRITIS
This project examines gene expression patterns and epigenetic mechanisms that characterize cartilage homeostasis, healthy aging and osteoarthritis using human knees.

Funding
NIH/NIA R01 AG049617 01/15/16-11/30/25
ROLE: Lotz PI

Publications
Identification of transcription factors responsible for dysregulated networks in human osteoarthritis cartilage by global gene expression analysis.
Fisch KM, Gamini R, Alvarez-Garcia O, Akagi R, Saito M, Muramatsu Y, Sasho T, Koziol JA, Su AI, Lotz MK.
Osteoarthritis Cartilage. 2018 Nov;26(11):1531-1538. doi: 10.1016/j.joca.2018.07.012. Epub 2018 Aug 3. PMID: 30081074

Impaired Proteasomal Function in Human Osteoarthritic Chondrocytes Can Contribute to Decreased Levels of SOX9 and Aggrecan.
Serrano RL, Chen LY, Lotz MK, Liu-Bryan R, Terkeltaub R.
Arthritis Rheumatol. 2018 Jul;70(7):1030-1041. doi: 10.1002/art.40456. Epub 2018 May 27. PMID: 29457374

Platelet-derived growth factor-coated decellularized meniscus scaffold for integrative healing of meniscus tears.
Lee KI, Olmer M, Baek J, D'Lima DD, Lotz MK.
Acta Biomater. 2018 Aug;76:126-134. doi: 10.1016/j.actbio.2018.06.021. Epub 2018 Jun 14. PMID: 29908335

Suppression of circadian clock protein cryptochrome 2 promotes osteoarthritis.
Bekki H, Duffy T, Okubo N, Olmer M, Alvarez-Garcia O, Lamia K, Kay S, Lotz M. Osteoarthritis Cartilage. 2020 Jul;28(7):966-976. doi: 10.1016/j.joca.2020.04.004. Epub 2020 Apr 24.PMID: 32339698

Mohawk is a transcription factor that promotes meniscus cell phenotype and tissue repair and reduces osteoarthritis severity.
Lee KI, Gamini R, Olmer M, Ikuta Y, Hasei J, Baek J, Alvarez-Garcia O, Grogan SP, D'Lima DD, Asahara H, Su AI, Lotz MK.
Sci Transl Med. 2020 Oct 28;12(567):eaan7967. doi: 10.1126/scitranslmed.aan7967. PMID: 33115953

Both microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis.
Ito Y, Matsuzaki T, Ayabe F, Mokuda S, Kurimoto R, Matsushima T, Tabata Y, Inotsume M, Tsutsumi H, Liu L, Shinohara M, Tanaka Y, Nakamichi R, Nishida K, Lotz MK, Asahara H.
Nat Commun. 2021 Jul 6;12(1):4148. doi: 10.1038/s41467-021-24460-7.PMID: 34230481

Transcriptomic analyses of joint tissues during osteoarthritis development in a rat model reveal dysregulated mechanotransduction and extracellular matrix pathways.
Hu Y, Li K, Swahn H, Ordoukhanian P, Head SR, Natarajan P, Woods AK, Joseph SB, Johnson KA, Lotz MK.
Osteoarthritis Cartilage. 2022 Oct 28:S1063-4584(22)00880-9. doi: 10.1016/j.joca.2022.10.003. Online ahead of print. PMID: 36354073

Senescent cell population with ZEB1 transcription factor as its main regulator promotes osteoarthritis in cartilage and meniscus.
Swahn H, Li K, Duffy T, Olmer M, D'Lima DD, Mondala TS, Natarajan P, Head SR, Lotz MK.
Ann Rheum Dis. 2022 Dec 23:ard-2022-223227. doi: 10.1136/ard-2022-223227. Online ahead of print. PMID: 36564153

MAPPING THE JOINT-NERVE INTERACTOME OF THE KNEE
The goal is to use transcriptomic analyses at single cell and tissue levels to determine interactions between joint tissues and the peripheral nervous system that are involved in joint pain.
The project is part of the Restoring Joint Health and Function to Reduce Pain (RE-JOIN) Consortium is a new program within the NIH Helping to End Addiction Long-term (HEAL) program. The overall goals of HEAL are ’Understanding, managing, and treating pain and consequently ‘Improving prevention and treatment for opioid misuse and addiction’. Joint and back pain are the major indications for the prescription of pain medications, including opioids. The RE-JOIN Consortium aims to understand how patterns of sensory neuron networks in joints change with disease and aging. Our goal is to use transcriptomic analyses at single cell and tissue spatial levels of the knee joint tissues and dorsal root ganglia to determine interactions between joint tissues and the peripheral nervous system that are involved in joint pain. Mechanisms and mediators of these interactions would be potential new targets for tissue destruction and joint pain.

Funding
NIH UC2 AR0821860 9/23/22-08/31/27
ROLE: Lotz (Co-PI) with Anne-Marie Malfait and Richard Miller

FOXO TRANSCRIPTION FACTORS AS CRITICAL REGULATORS OF INTERVERTEBRAL DISC AGING
The objective of this project is to determine the role of FoxO in intervertebral disc homeostasis, how FoxO deficient promotes intervertebral disc degeneration and whether enhancing FoxO activation has therapeutic potential.

Funding
NIH/NIA R01 AG062533 08/01/19-04/30/24
ROLE: Lotz (PI)

Publications
Age-related reduction in the expression of FOXO transcription factors and correlations with intervertebral disc degeneration.
Alvarez-Garcia O, Matsuzaki T, Olmer M, Masuda K, Lotz MK.
J Orthop Res. 2017 Dec;35(12):2682-2691. doi: 10.1002/jor.23583. Epub 2017 May 4. PMID: 28430387

FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration.
Alvarez-Garcia O, Matsuzaki T, Olmer M, Miyata K, Mokuda S, Sakai D, Masuda K, Asahara H, Lotz MK.
Aging Cell. 2018 Oct;17(5):e12800. doi: 10.1111/acel.12800. Epub 2018 Jul 2. PMID: 29963746

The cellular landscape of the healthy human intervertebral disc: identification of new immature cell populations and their relationship with mature populations at single cell resolution.
Mertens J, Swahn H, Olmer M, Myers K, Mondala TS, Natarajan P, Head SR, Alvarez-Garcia O, Lotz MK.
Submitted

Shared and compartment-specific processes in nucleus pulposus and annulus fibrosus during intervertebral disc degeneration.
Swahn H, Mertens J, Olmer M, Myers K, Mondala TS, Natarajan P, Head SR, Alvarez-Garcia O, Lotz MK.
Submitted

HIGH RESOLUTION 3D MAPPING OF CELLULAR HETEROGENEITY WITHIN MULTIPLE TYPES OF MINERALIZED TISSUES

The Human BioMolecular Atlas Program (HuBMAP) is working to create a Human Reference Atlas at the cellular level. We will map the cellular composition of the human knee joint at single cell resolution.

This project is part of the HuBMAP consortium and applies single cell and spatial transcriptomics to build three-dimensional maps of normal human articular cartilage.

Funding
NIH/NIAMS 5 U54 AR078664 09/01/22-08/31/23
ROLE: Lotz Co-PI with David Rowe

Publications
Senescent cell population with ZEB1 transcription factor as its main regulator promotes osteoarthritis in cartilage and meniscus.
Swahn H, Li K, Duffy T, Olmer M, D'Lima DD, Mondala TS, Natarajan P, Head SR, Lotz MK.
Ann Rheum Dis. 2022 Dec 23:ard-2022-223227. doi: 10.1136/ard-2022-223227. Online ahead of print. PMID: 36564153

MECHANO SIGNALS REGULATING TENDON AND LIGAMENT HOMEOSTASIS
The goal is to determine the function of mechanoreceptors in tendon development, homeostasis, and regeneration.

Funding
NIH/NIAMS R01 AR080127 09/20/22-08/31/27
ROLE: Lotz Co-I; Asahara PI

Publications
The mechanosensitive ion channel PIEZO1 is expressed in tendons and regulates physical performance.
Nakamichi R, Ma S, Nonoyama T, Chiba T, Kurimoto R, Ohzono H, Olmer M, Shukunami C, Fuku N, Wang G, Morrison E, Pitsiladis YP, Ozaki T, D'Lima D, Lotz M, Patapoutian A, Asahara H.
Sci Transl Med. 2022 Jun;14(647):eabj5557. doi: 10.1126/scitranslmed.abj5557. Epub 2022 Jun 1. PMID: 35648809

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