This Growth Factor May Play a Bigger Role in Osteoarthritis Than Previously Thought

Healthy mice receiving injections of nerve growth factor (NGF) into their knee joints developed multiple joint abnormalities seen in osteoarthritis (OA), suggesting that the substance does a lot more than just stimulate pain signaling, researchers said.

Among the OA features resulting from the NGF injections: swollen joints, synovial pathology including fibrosis, increased bone mineral density in tibial bones, and growth of pre-osteophytes, reported Anne-Marie Malfait, MD, PhD, of Rush University in Chicago, and colleagues.

To be sure, pain pathways were stimulated as well, the group noted in Arthritis & Rheumatology. Hyperalgesia in the knee joint was also noted after NGF injections, along with increased sprouting of nociceptors.

The only aspect of human OA not seen with the injections was definite cartilage damage. The study only lasted a few weeks, however, and Malfait and colleagues suggested that “longer exposure to NGF might well be detrimental to cartilage,” a possibility that no one, apparently, had previously thought to investigate.

That NGF and OA are connected in some way has been known for a long time. In 1996, researchers tied NGF to inflammatory pain specifically; by 2003, other groups were reporting that synovial fibroblasts could secrete it. Research showed that multiple cell types within the joint express NGF receptors, an indication that NGF is no stranger there.

Such studies prompted drug developers to test anti-NGF antibodies as an OA therapy. The most promising such agent was tanezumab, which showed encouraging efficacy in a phase II trial published in 2010. But in subsequent trials, a few patients saw their OA worsen quickly. By 2021, tanezumab had been cancelled and NGF was mostly written off as an OA treatment target.

Throughout that saga, it was assumed that NGF’s role was merely to promote pain signaling. But with its apparent ubiquity in joint biology, Malfait’s group decided to look more closely at what else NGF might do.

Their key experiments included controls receiving saline injections, to ensure that what the researchers saw with NGF was not just the result of inserting needles into the joint. Animals were 12-15 weeks old and injections were given twice a week for 4 weeks, except in one experiment meant to collect dorsal route ganglia samples for evaluation of gene expression, in which the treatment period was 10 days. Animals were killed a few days after completing the scheduled injection regimen and their tissues harvested for analysis.

Result highlights included:

• Hyperalgesia in the injected knee was significantly worse with NGF compared with placebo
• NGF injections at 500 ng induced definite swelling, although 50-ng injections did not
• Knee synovium showed “increased subintimal cellularity, fibrosis, and lining hyperplasia” with the 500-ng dose
• Chondrophytes or pre-osteophytes appeared in the medial compartment, more strongly with the high versus low dose
• Bone mineral density and trabecular bone thickness increased in the medial tibial subchondral bone
• Nociceptor sprouting was observed in the medial synovium with NGF but not placebo
• Nociceptors also developed in pre-osteophytes as they grew in the NGF-treated mice
• Across multiple cell types, many genes showed altered expression with NGF exposure, suggesting an array of cellular responses not directly related to pain signaling

Malfait and colleagues summarized their findings in this way: “[T]he picture that arises is a complex and time-dependent interaction between pain, NGF signaling, nerve growth, and joint damage, and we propose that in-depth studies with anti-NGF at different time points in the course of experimental OA are needed.”

Importantly, what their study didn’t do is provide an explanation for the rapidly progressing OA (RPOA) that doomed the earlier generation of anti-NGF drugs. The researchers acknowledged that the mechanisms underlying that effect remain mysterious. Just over a week ago, though, another group reported on an alternative approach targeting a different member of the broader neurotrophin family that also comprises NGF. In a placebo-controlled phase II trial, an investigational agent called LEVI-04 significantly alleviated OA patients’ pain, with no participants showing serious RPOA.

That study, however, did not examine cellular or structural outcomes, and with about 260 patients receiving LEVI-04, it might not have been big enough for RPOA to show its head. In one of tanezumab’s phase III trials, with some 560 treated with the drug, four cases of serious RPOA were observed.