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"Nerve growth factor (NGF) is a specialized protein, also called a neurotrophin, that is critical for the development and survival of nerves responsible for our senses and the body's fight-or-flight response. While the presence of NGF is crucial during the embryonic stage, its presence in adults is often an indication of inflammation, as it is a key mediator of pain for conditions like osteoarthritis (OA). Now, a study ... shows that NGF is much more than a pain messenger—it can actually change the structure of a joint.
When the researchers injected NGF into healthy knee joints of mice, the joints gradually became swollen and much more sensitive to pain.
Over time, they began to look and behave as if they had osteoarthritis. Even though no visible damage appeared on the protective knee cartilage, the bone underneath became denser and small bony growths, also known as pre-osteophytes, began to form post the NGF injections. ..."
From the abstract:
"Objective
Nerve growth factor (NGF), a key mediator of pain, is increased in osteoarthritic (OA) joints.
Antibodies against NGF show analgesic effects in painful knee OA, but clinical development was stopped due to side-effects in the joints. Knowledge about the biological effects of NGF on joint tissues is limited. Therefore, we explored the effects of repeated intra-articular (IA) injections of NGF into naïve murine knee joints on sensitization, joint innervation and histopathology.
Methods
Naïve 10 to 15-week-old male wildtype C57BL/6 mice were injected with NGF (50 or 500 ng) or vehicle IA twice a week for 4 weeks, and assessed effects on knee swelling, knee hyperalgesia, joint histopathology, and bone. Single cell RNA sequencing (scRNAseq) of the synovium was performed. NaV1.8-tdTomato reporter mice were used to assess joint innervation. Dorsal root ganglia (DRGs) of mice underwent bulk RNA sequencing after 3 IA injections of NGF or vehicle.
Results
Compared to vehicle, repeated IA injections of NGF caused dose-dependent increases in knee swelling, knee hyperalgesia, synovial pathology, bone mineral density in the medial subchondral bone, and medial pre-osteophytes, but no overt cartilage damage.
NGF caused increased sprouting of nociceptors in the medial synovium, which was preceded by upregulation of axonal growth pathways in the DRGs. ScRNAseq of the synovium revealed upregulated genes related to neuronal sprouting, synovial fibrosis, and ossification, with a key role for lining fibroblasts.
Conclusions
In naive mouse knees, NGF induced many pathological changes observed in OA, including nociceptor sprouting, suggesting a critical role for NGF in OA pathogenesis."
Nerve growth factor is sufficient to cause multiple osteoarthritis-relevant pathological features in naïve murine knee joints (open access)
Fig. 1 Schematic illustration of the 5 experiments performed, showing injection protocols, mouse strains (n), experimental endpoints, and outcome measures. ScRNAseq= single cell RNA sequencing. (Source)
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