Background/Purpose Neurotrophins (Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)) are initially synthesized as pro-neurotrophins (proNGF and proBDNF), which are hydrolyzed to produce the mature proteins. BDNF is reported to be a stimulus for osteoclast differentiation in multiple myeloma. Anti-NGF is currently in trials for relief of chronic pain in patients with osteoarthritis but trials are on hold due to the common occurrence of rapidly progressive osteonecrosis resembling Charcot’s arthropathy. We therefore sought to determine whether pro-NGF, which stimulates different receptors than the mature protein, plays a role in bone homeostasis we examined mice that overexpressed poorly hydrolyzed pro-NGF.

Methods Wild type C57BL/6 (WT) and proNGF/+ (mice that overexpress a poorly hydrolysable proNGF) mice were sacrificed and prepared for microCT. Osteoclast and osteoblast differentiation was studied in primary murine bone marrow precursors as number of TRAP-positive cells or Alizarin Red-positive stain after challenge with the presence/absence of recombinant neurotrophins. Neurotrophin receptors (p75, Sortilin, Sorcs2) were analyzed by Western Blot.

Results

microCT revealed an increase in cortical and trabecular bone in proNGF/+ mice when compare to WT. This change correlated with a decrease in osteoclast differentiation in cells from proNGF/+ mice (30±3% decrease, p<0.001, n=4) and increased osteoblast differentiation in proNGF/+ (46±5% increase, p<0.5, n=4). Treatment with proNGF markedly inhibits osteoclast differentiation (60±2% decrease, p<0.001, n=5) without affecting osteoblast differentiation (10±5% increase, p=ns, n=5). In contrast, recombinant NGF increased osteoclast differentiation (17±2% increase, p<0.05, n=5) with a decrease in osteoblast formation (62±3% decrease, p<0.001, n=5). p75, Sortilin and Sorcs2 receptors were expressed in osteoclasts and osteoblasts.

Conclusion These results indicate that the rapid bone destruction seen in patients treated with anti-NGF antibodies is most likely due to reduction of pro-NGF levels required for maintenance of bone homeostasis.  Moreover, our results suggest that administering a therapeutically effective amount of proNGF may provide a novel therapeutic approach to promote bone growth and prevent Charcot’s arthropathy, a common problem in patients, such as diabetics, with peripheral neuropathy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pro-nerve-growth-factor-prongf-stimulates-bone-growth-by-stimulating-osteoblasts-and-inhibiting-osteoclast-differentiation-an-explanation-for-anti-ngf-mediated-osteonecrosis-prongf-is-a-novel-ther/