Nerves may be key to blocking abnormal bone growth in tissue
Drugs being investigated for pain relief may prevent heterotopic
ossification, study suggests.

Date:
November 4, 2021
Source:
UT Southwestern Medical Center
Summary:
Blocking a molecule that draws sensory nerves into musculoskeletal
injuries prevents heterotopic ossification (HO), a process in which
bone abnormally grows in soft tissue during healing, researchers
reported. The findings suggest that drugs currently being tested
in clinical trials to inhibit this molecule for pain relief could
also protect against this challenging condition.



FULL STORY ========================================================================== Blocking a molecule that draws sensory nerves into musculoskeletal
injuries prevents heterotopic ossification (HO), a process in which
bone abnormally grows in soft tissue during healing, UT Southwestern researchers reported in a study. The findings, published in Nature Communications, suggest that drugs currently being tested in clinical
trials to inhibit this molecule for pain relief could also protect
against this challenging condition.


========================================================================== "Heterotopic ossification is an incredibly debilitating condition for
which we have no truly effective therapies," said study leader Benjamin
Levi, M.D., Associate Professor of Surgery and in the Children's Medical
Center Research Institute at UT Southwestern and the Charles and Jane
Pak Center for Mineral Metabolism and Clinical Research. "To be able
to prevent HO from occurring after an injury while also decreasing
pain would be a substantial step forward." HO occurs in a significant
number of patients with musculoskeletal injuries or who undergo some
surgeries. For example, about 20% of patients undergoing an initial
hip replacement develop this abnormal bone growth, and for a second
replacement of the same hip, that number rises to up to 80%. HO is also
common in patients with large-area burns, traumatic elbow injuries,
spinal cord injuries, and pelvic fractures, where it causes contractures
that limit mobility. Although pain during healing is an obvious feature
of these injuries and surgeries, Dr. Levi explained, it's been unclear
whether pain-sensing nerves play a role in its development.

To investigate this question, Dr. Levi and Johns Hopkins colleague
Aaron W.

James, M.D., Ph.D., co-led a team of researchers from six institutions
to determine how HO is affected by sensory nerves. Using a mouse model,
the researchers observed that sciatic nerve axons -- long extensions
of neurons - - grew into the injury site before HO occurred. When the
nerve axons were not present, HO did not develop.

In an effort to identify the signal that draws sensory nerve axons into
the injury site, the researchers surveyed gene activity to determine
which genes might be over- or under-producing proteins after injury. They
found that the amount of one protein, called nerve growth factor (NGF), increased several-fold after injury, and it came from cells on the
outside of blood vessels. Because nerve fibers usually travel the same
routes as blood vessels, NGF seemed like a likely beacon to draw axons in.

Sure enough, when the researchers used a genetic technique to shut down
NGF- signaling at the injury site, HO did not develop. The researchers
achieved similar success by using small molecules or an investigational
drug to block TrkA, the receptor to which NGF binds.

Dr. Levi noted that several drugs that aim to relieve pain by blocking
NGF are currently in phase 3 clinical trials at other institutions. These
drugs could serve a dual purpose in patients at risk for HO by preventing
this condition from developing.

========================================================================== Story Source: Materials provided by UT_Southwestern_Medical_Center. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Seungyong Lee, Charles Hwang, Simone Marini, Robert J. Tower,
Qizhi Qin,
Stefano Negri, Chase A. Pagani, Yuxiao Sun, David M. Stepien,
Michael Sorkin, Carrie A. Kubiak, Noelle D. Visser, Carolyn
A. Meyers, Yiyun Wang, Husain A. Rasheed, Jiajia Xu, Sarah Miller,
Amanda K. Huber, Liliana Minichiello, Paul S. Cederna, Stephen
W. P. Kemp, Thomas L.

Clemens, Aaron W. James, Benjamin Levi. NGF-TrkA signaling dictates
neural ingrowth and aberrant osteochondral differentiation after
soft tissue trauma. Nature Communications, 2021; 12 (1) DOI:
10.1038/s41467- 021-25143-z ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211104162636.htm

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