Bruce N. Cronstein

Bruce N. Cronstein, MD

Dr. Paul R. Esserman Professor of Medicine, Department of Medicine

Professor, Department of Biochemistry and Molecular Pharmacology

Professor, Department of Pathology

Keywords
adenosine, adenosine receptors, bone biology, inflammation, fibrosis, wound healing, chondrocyte biology, purine metabolism, arthritis, osteoarthritis
Summary

Our research has focused on adenosine, which is released from most cells and tissues as a result of ATP catabolism, in response to stressors such as hypoxia and inflammatory injury. Adenosine regulates numerous physiological functions by interacting with one or more of at least four known receptors, A1, A2A, A2B, and A3—all of which are members of the family of G protein–coupled receptors. Nearly every cell and tissue type examined expresses at least one adenosine receptor type, usually more than one.

My laboratory first demonstrated the presence and function of adenosine receptors on human polymorphonuclear leukocytes, including their role in regulating inflammation. Inflammation is a critical target for treating tissue injury and preventing superinfection at wound sites. Nonetheless, excess inflammation that persists can lead to significant tissue injury and destruction. In this regard, we demonstrated that adenosine is capable of resolving inflammation and that it is endogenously released at inflamed sites, where it can help to terminate the inflammatory state and promote wound healing. 

We have since shown that adenosine, acting at its receptors, mediates the anti-inflammatory effects of low-dose weekly methotrexate, the drug that remains the “gold standard” in the treatment of rheumatoid arthritis. Moreover, adenosine, acting at its receptors, also mediates many of the toxicities of methotrexate, including the promotion of fatty liver and hepatic fibrosis (A1, A2A, and A2B receptors) and rheumatoid nodulosis (A1 receptors).

In other studies we have demonstrated that excess adenosine is involved in in scar formation and other fibrotic reactions in skin. This fibrosis can be pathologic, and blockade of adenosine A2A receptors can diminish scarring and radiation fibrosis in the skin as well as diffuse dermal fibrosis and hepatic fibrosis. Since caffeine is a non-selective antagonist of adenosine receptors, these results demonstrate a mechanism for the strong epidemiologic association of coffee drinking with protection from death due to liver disease.

We have also examined the role of adenosine and its receptors in bone and joint physiology and pharmacology. We have reported that the adenosine A1, A2A, and A2B receptors regulate bone formation, and that adenosine receptor agonists and agents that increase local adenosine concentrations can be used to promote bone regeneration. These studies are now making their way into the clinic, where resorbable scaffolds coated with agents that increase extracellular adenosine concentrations show great promise for promoting closure of critical bone defects, such as those occurring at sites of trauma. 

The role of purine metabolism in chondrocyte and cartilage biology was recently investigated in my laboratory and we made the surprising finding that adenosine is a critical regulator of chondrocyte metabolism via the adenosine A2A receptor. ATP is released from chondrocytes and converted extracellularly to adenosine which, acting through the A2A receptor, promotes matrix production and diminishes destruction of cartilage. With inflammation and advancing age chondrocytes release less ATP which leads to diminished extracellular adenosine and disruption of chondrocyte production of cartilage matrix. Intra-articular injection of long-acting (liposomal) adenosine prevents progression of osteoarthritis in animal models. We hope to translate this to the clinic as well.

Phone

212-263-6404

Academic office

550 First Ave.

Second Floor, MSB251

New York, NY 10016

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Dr. Paul R. Esserman Professor of Medicine, Department of Medicine

Professor, Department of Biochemistry and Molecular Pharmacology

Professor, Department of Pathology

Director Program in Collaborative Research

Director, Clinical and Translational Science Institute

Director, Division of Translational Medicine

MD from University of Cincinnati

Fellowship, New York University School of Medicine, Rheumatology

Residency, Lenox Hill Hospital, Internal Medicine

Residency, University of Cincinnati Medical Center, Internal Medicine

Residency, New York University School of Medicine, Pathology

Haskó, György; Antonioli, Luca; Cronstein, Bruce N

Biochemical pharmacology. 2018 May 22; 151:307-313

Bekisz, Jonathan M; Lopez, Christopher D; Corciulo, Carmen; Mediero, Aranzazu; Coelho, Paulo G; Witek, Lukasz; Flores, Roberto L; Cronstein, Bruce N

Inflammation. 2018 Apr 14;

Yang, Lu; Fanok, Melania H; Mediero-Munoz, Aranzazu; Fogli, Laura K; Corciulo, Carmen; Abdollahi, Shahla; Cronstein, Bruce N; Scher, Jose U; Koralov, Sergei B

Arthritis & rheumatology. 2018 Feb 13;

Mediero, Aránzazu; Wilder, Tuere; Shah, Lopa; Cronstein, Bruce N

FASEB journal. 2018 Feb 02; fj201700217R-fj201700217R

Bekisz, Jonathan M; Flores, Roberto L; Witek, Lukasz; Lopez, Christopher D; Runyan, Christopher M; Torroni, Andrea; Cronstein, Bruce N; Coelho, Paulo G

Journal of cranio-maxillo-facial surgery. 2017 Nov 21; 46(2):237-244

Lopez, Christopher D; Diaz-Siso, J Rodrigo; Witek, Lukasz; Bekisz, Jonathan M; Cronstein, Bruce N; Torroni, Andrea; Flores, Roberto L; Rodriguez, Eduardo D; Coelho, Paulo G

Journal of surgical research. 2017 Nov 17; 223:115-122

Feig, Jessica L; Mediero, Aranzazu; Corciulo, Carmen; Liu, Hailing; Zhang, Jin; Perez-Aso, Miguel; Picard, Laura; Wilder, Tuere; Cronstein, Bruce

PLoS one. 2017 Nov 16; 12(11):e0188135-e0188135

Fruchter, Renee; Ahmad, Meleha; Pillinger, Michael; Galeano, Claudia; Cronstein, Bruce N; Gold-von Simson, Gabrielle

Clinical & translational science. 2017 Nov 07;

Training Young Doctors to Think Like Scientists

Study Finds New Treatment Approach for Osteoarthritis