The Effect of Celecoxib and muMab911 on Strain Adaptive Bone Remodeling and Fracture Repair in Female Mice: Implications for Rapidly Progressive Osteoarthritis

Ruggiero, N.; Ciuciu, A.; Sedigh, A.; Rajpar, I.; Shelton, D.; Belanger, P.; Gropp, K.; Collins, J. A.; Freeman, T. A.; Tomlinson, R. E.

doi:10.1101/2025.03.24.645018

bioRxiv · 10.1101/2025.03.24.645018

The Effect of Celecoxib and muMab911 on Strain Adaptive Bone Remodeling and Fracture Repair in Female Mice: Implications for Rapidly Progressive Osteoarthritis

Ruggiero, N.·Ciuciu, A.·Sedigh, A.·Rajpar, I.·Shelton, D.·Belanger, P.·Gropp, K.·Collins, J. A.·Freeman, T. A.·Tomlinson, R. E.

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Abstract

Debilitating pain is the primary clinical feature of osteoarthritis (OA) that drives the enormous healthcare costs. Osteoarthritis-related pain is often treated with non-steroidal anti-inflammatory drugs (NSAIDs), which effectively relieve pain and inflammation by inhibition of prostaglandin synthesis. Antibodies directed against nerve growth factor (NGF) were tested some time ago as an alternative potential analgesic for musculoskeletal pain, including osteoarthritis-related pain. Unfortunately, clinical development of these drugs was put on hold due to adverse outcomes - primarily rapidly progressive osteoarthritis. Both prostaglandin synthesis and NGF have been implicated as critical mediators of strain adaptive bone remodeling, which may play a role in rapid osteoarthritis progression. Therefore, this study was designed to investigate the effects of celecoxib, an NSAID, and muMab911, an anti-NGF antibody, as well as the combination therapy on strain adaptive bone remodeling, bone mass and geometry, and bone healing in a murine model. Adult female C57BL/6J mice received celecoxib through drinking water, up to 3 IP injections of muMab911, or both treatments over a period of two weeks. As expected, all treatments were effective for relieving injury-associated pain. Consistent with previous studies, we found that celecoxib alone and in combination with muMab911 impaired periosteal load-induced bone formation induced by axial forelimb compression. Furthermore, both treatments had minimal effects on osteoblast and osteocyte populations, bone structural and material properties, and cortical and trabecular bone mass. Mice subjected to damaging axial forelimb compression did not have impaired healing or callus morphology due to treatment. Nonetheless, both drugs decreased NGF expression during fracture healing. In total, our results indicate that these medications both suppress NGF expression and load-induced bone formation which may support rapid OA disease progression by diminishing strain adaptive bone remodeling in subchondral bone of OA patients.

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Ruggiero, N., Ciuciu, A., Sedigh, A., Rajpar, I., Shelton, D., Belanger, P., Gropp, K., Collins, J. A., Freeman, T. A., Tomlinson, R. E.. 2025-03-27. The Effect of Celecoxib and muMab911 on Strain Adaptive Bone Remodeling and Fracture Repair in Female Mice: Implications for Rapidly Progressive Osteoarthritis. https://doi.org/10.1101/2025.03.24.645018

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