Effects of a Monoclonal Antibody Raised Against Nerve Growth Factor on Skeletal Pain and Bone Healing After Fracture of the C57BL/6J Mouse Femur

Abstract

A closed femur fracture pain model was developed in the C57BL/6J mouse. One day after fracture, a monoclonal antibody raised against nerve growth factor (anti-NGF) was delivered intraperitoneally and resulted in a reduction in fracture pain-related behaviors of ∼50%. Anti-NGF therapy did not interfere with bone healing as assessed by mechanical testing and histomorphometric analysis.Introduction: Current therapies to treat skeletal fracture pain are limited. This is because of the side effect profile of available analgesics and the scarcity of animal models that can be used to understand the mechanisms that drive this pain. Whereas previous studies have shown that mineralized bone, marrow, and periosteum are innervated by sensory and sympathetic fibers, it is not understood how skeletal pain is generated and maintained even in common conditions such as osteoarthritis, low back pain, or fracture. Materials and Methods:In this study, we characterized the pain-related behaviors after a closed femur fracture in the C57BL/6J mouse. Additionally, we assessed the effect of a monoclonal antibody that binds to and sequesters nerve growth factor (anti-NGF) on pain-related behaviors and bone healing (mechanical properties and histomorphometric analysis) after fracture. Results: Administration of anti-NGF therapy (10 mg/kg, days 1, 6, and 11 after fracture) resulted in a reduction of fracture pain-related behaviors of ∼50%. Attenuation of fracture pain was evident as early as 24 h after the initial dosing and remained efficacious throughout the course of fracture pain. Anti-NGF therapy did not modify biomechanical properties of the femur or histomorphometric indices of bone healing. Conclusions: These findings suggest that therapies that target NGF or its cognate receptor(s) may be effective in attenuating nonmalignant fracture pain without interfering with bone healing.

Methotrexate chemotherapy triggers touch-evoked pain and increased CGRP-positive sensory fibres in the tibial periosteum of young rats

“…In order to assess bone pain severity associated with MTX chemotherapy, we adopted some well established animal behavioural tests for measuring bone pain induced by bone cancer and fracture [18,20]. These tests were designed to assess ongoing and breakthrough pain, the two most clinically recognized types of pain due to bone damage [24,25].…”

“…These animal behavioural tests (outlined in Fig. 1) are based on well-established protocols routinely used to assess cancer and fracture-induced bone pain in rats and mice [16][17][18][19][20][21].…”

“…Every lift of hind limb not related to walking or grooming was considered to be one flinch. The guarding duration of the lift was recorded until the paw again touched the walking surface [19,20].…”

“…In addition, as another measurement of mobility, loading on both hind limbs was analysed by recording the number of total spontaneous vertical stands during the 2 min open field test. This was based on a similar test used previously to examine the effect of femur fracture on the loading of mouse hind limbs [20]. A spontaneous vertical stand is when during normal ambulation an animal stands on both hind limbs supporting its entire body weight.…”

Treating the Pain of Osteoarthritis — Where Do We Go from Here?

“…NGF is a neurotrophin, which is released from inflamed tissue and sensitizes peripheral nociceptors. Animal models have shown that by blocking the action of NGF with a soluble receptor or monoclonal antibody, pain can be significantly reduced 10,11 . …”