Osteoarthritis – Nerve therapy possibilities

My mother is 76 years old.  She lives with me. So, her medical needs are very important to me.  This is why family relationships are so important.  You want your children to love you so that they care and worry about you when your old and weak and not ABLE to, which can lead to a depression so deep that one STOPS feeling the need to even care for oneself.  The will to live is no longer great.  Yet.  My mother is a awesome human being.  She has the will to live and doesn’t want to die.  She has osteoarthritis so bad that both hips have been replaced.  She’s had congestive heart failure.  She was born with one kidney (congenital kidney) which didn’t let her grow beyond 5’2″ and now she is only 4’7″.  But she is full of wisdom.  She knows RIGHT from WRONG.  She guides and is gentle.  Yet, she is steady and STRONG.  My mother is like silk.  Fragile, yet woven together she can repel an arrow and keep one warm in winter.  She is a true WOMAN.  My father died when she was 57 years old.  She never once looked to another man.  This is why relationships ARE important.  They keep the families SANE.  That keep society functioning and cohesive and able to expand.

This is why I share what I learn when I can.

Nerve Growth Factor and Pain:

John N. Wood, D.Sc.

September 29, 2010 (10.1056/NEJMe1004416)

Osteoarthritis, a common, painful condition, occurs at a rate of 1% per year and affects the majority of people who are over 55 years of age. In a proof-of-concept, phase 2 study in this issue of theJournal, Lane and colleagues1 report that blocking the activity of nerve growth factor with a neutralizing humanized monoclonal antibody (tanezumab) can relieve pain from osteoarthritis. This finding raises the possibility of using neutralizing antibodies therapeutically, similar to the use of antibodies against tumor necrosis factor (TNF) in patients with rheumatoid arthritis. However, recent results of a phase 3 study, mentioned by Lane et al. in the Discussion section of their article, indicate that although tanezumab has analgesic efficacy, it precipitates joint failure in some recipients. Accordingly, at the request of the Food and Drug Administration (FDA), a number of clinical trials with tanezumab have been suspended.

Nerve growth factor acts through two distinct types of high-affinity cell-surface receptors: tropomyosin-related kinase A (TrkA) — a tyrosine kinase — and p75, a member of the TNF-receptor family. Although there is evidence that p75 has a role in pain syndromes that involve nerve damage (so-called neuropathic pain), the role of this receptor in inflammatory pain seems to be less important than that of TrkA.2,3

Nerve growth factor, a dimeric molecule, activates TrkA by instigating the dimerization of two TrkA receptor molecules, resulting in their autophosphorylation and the initiation of a cascade of downstream regulatory events. Humans and mice harboring loss-of-function mutations in the TrkA gene (mutations that mute signaling by TrkA) lose sensory and sympathetic neurons (and pain sensation) — showing that nerve growth factor has an essential trophic role in supporting the survival of these neurons. The cell types that express TrkA include not only peripheral sensory neurons but also small subgroups of central nervous system neurons.4

Interestingly, non-neuronal cells, including macrophages and monocytes, also express TrkA. The activation of TrkA on these cells can result in the release of mediators that sensitize sensory neurons and change pain thresholds.5 However, an overwhelming body of evidence supports a role for nerve growth factor in changing pain thresholds through TrkA-mediated sensitization of peripheral neurons.

Evidence for a role of nerve growth factor both in supporting the development of sensory neurons — particularly those involved in sensing tissue damage (nociceptors) — and in changing pain thresholds has accumulated over half a century. In 1964, Levi-Montalcini used antiserums to nerve growth factor activity to investigate neuronal survival in culture.6 Twenty-five years later, the analgesic effects of antiserums that neutralize nerve growth factor were reported in animal models.7Several papers showed the hyperalgesic properties of nerve growth factor in rodents.8,9 Neutralizing molecules (soluble TrkA fusion proteins) with precise specificity for nerve growth factor were shown to have potent analgesic activity, providing the rationale for the development of antibodies that block nerve growth factor.10

Fundamental studies of neuronal growth factors, in combination with the development of monoclonal antibodies and the application of recombinant DNA technology to humanize antibodies, have produced for human use an agent that has analgesic potency for pain that does not respond to aspirin-like drugs or opioids. Indeed, the use of neutralizing antibodies to nerve growth factor has shown that passive immunization seems to provide an effective analgesic therapy for osteoarthritis. However, the associated risk of joint destruction, which has resulted in the suspension of much of the clinical research involving tanezumab, is likely to limit the clinical application of this approach to pain relief.

The side effects noted with tanezumab include some paresthesias and headaches. But the most problematic issue — which has emerged during the phase 3 study and has resulted in the FDA putting the phase 3 study and two other studies of tanezumab on hold — has been joint failure, which was most likely caused by excessive wear and tear in the absence of joint pain. Pain has an important role in the avoidance of self-harm, but chronic inflammatory pain has generally been considered to be wholly undesirable. The study by Lane et al. suggests that a complete quenching of pain in patients with osteoarthritis may not necessarily be a good thing.



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