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The evolution of nerve growth factor inhibition in clinical medicine

Nature Reviews Rheumatology volume 17, pages 34–46 (2021)Cite this article

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Abstract

Nerve growth factor (NGF) is a neurotrophin that activates nociceptive neurons to transmit pain signals from the peripheral to the central nervous system and that exerts its effects on neurons by signalling through tyrosine kinase receptors. Antibodies that inhibit the function of NGF and small molecule inhibitors of NGF receptors have been developed and tested in clinical studies to evaluate the efficacy of NGF inhibition as a form of analgesia in chronic pain states including osteoarthritis and chronic low back pain. Clinical studies in individuals with painful knee and hip osteoarthritis have revealed that NGF inhibitors substantially reduce joint pain and improve function compared with NSAIDs for a duration of up to 8 weeks. However, the higher tested doses of NGF inhibitors also increased the risk of rapidly progressive osteoarthritis in a small percentage of those treated. This Review recaps the biology of NGF and the studies that have been performed to evaluate the efficacy of NGF inhibition for chronic musculoskeletal pain states. The adverse events associated with NGF inhibition and the current state of knowledge about the mechanisms involved in rapidly progressive osteoarthritis are also discussed and future studies proposed to improve understanding of this rare but serious adverse event.

Key points

  • Chronic pain from osteoarthritis (OA) is highly prevalent, and effective non-opioid medications are few.

  • Nerve growth factor (NGF) is an important neurotrophin that activates nociceptive neurons to transmit pain signals from the peripheral to the central nervous system.

  • Treatment with anti-NGF antibodies inhibits joint pain and improves function in individuals with moderate to severe knee and hip OA.

  • NGF inhibition is associated with rapidly progressive large joint OA; many theories exist as to why but the exact mechanisms involved remain unknown.

  • Anti-NGF antibody treatments, if approved, should reduce pain and improve quality of life for individuals with knee and hip OA; however, safety monitoring programmes will be necessary.

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Fig. 1: The evolution of NGF inhibition in clinical medicine.
Fig. 2: Principles of neurogenic inflammation in joint pain.

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Author information

Author notes

  1. These authors contributed equally: Barton L. Wise, Matthias F. Seidel

Authors and Affiliations

  1. Center for Musculoskeletal Health, University of California Davis School of Medicine, Sacramento, CA, USA

    Barton L. Wise & Nancy E. Lane

  2. Department of Orthopaedic Surgery, University of California Davis School of Medicine, Sacramento, CA, USA

    Barton L. Wise

  3. Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, CA, USA

    Barton L. Wise & Nancy E. Lane

  4. Department of Rheumatology, Spitalzentrum Biel-Centre Hospitalier Bienne, Biel-Bienne, Switzerland

    Matthias F. Seidel

Authors
  1. Barton L. Wise
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  2. Matthias F. Seidel
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  3. Nancy E. Lane
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Contributions

M.F.S. and N.E.L. researched data for the article. All authors contributed substantially to discussions of content, wrote the article and reviewed or edited the manuscript before submission.

Corresponding author

Correspondence to Nancy E. Lane.

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Competing interests

B.L.W. declares that he received a research grant from Pfizer from 2011 to 2012. M.F.S. declares that he has been a consultant for Eli Lilly and Pfizer, and that he has received educational grants from these companies. N.E.L. declares that she has performed phase II and phase III clinical trials for Pfizer (2010–2012 and 2016–2019) and has been a consultant for Pfizer (2011–2019).

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Peer review information

Nature Reviews Rheumatology thanks F. Berenbaum and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Placode

Ectodermal structures in embryonic development that give rise to several different sensory systems.

Dorsal root ganglia

The cell bodies of sensory nerves that transmit action potentials to the spinal cord.

Retrograde axoplasmic transport

A process in which signalling molecules are moved from the periphery towards the cell body of an axon.

Antidromal transport

Axoplasmic transport of signalling molecules from the nucleus to nociceptors.

Allodynia

Painful sensation in response to non-painful stimuli.

Zygapophyseal joints

Vertebral (facet) joints that interconnect the vertebral bodies.

Paraesthesia

Abnormal skin sensation without stimulation.

Hypoaesthesia

Numbness of the skin with a reduction of sensations to sensory stimuli.

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Wise, B.L., Seidel, M.F. & Lane, N.E. The evolution of nerve growth factor inhibition in clinical medicine. Nat Rev Rheumatol 17, 34–46 (2021). https://doi.org/10.1038/s41584-020-00528-4

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