Preventing osteoporotic bone loss in mice by promoting balanced bone remodeling through M-CSF RGD , a dual antagonist to c-FMS and αvβ3 receptors

• Published in: International journal of biological macromolecules 2024-12, Vol.282 (Pt 2), p.136821
• Main Authors: Zur, Yuval, Katchkovsky, Svetlana, Itzhar, Amit, Abramovitch-Dahan, Chen-Viki, Stepensky, David, Papo, Niv, Levaot, Noam
• Format: Article
• Language: English
• Subjects: Alendronate - pharmacology; Animals; Bone Remodeling - drug effects; Bone Resorption - drug therapy; Bone Resorption - prevention & control; Female; Humans; Integrin alphaVbeta3 - antagonists & inhibitors; Integrin alphaVbeta3 - metabolism; Mice; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteogenesis - drug effects; Osteoporosis - drug therapy; Osteoporosis - metabolism; Osteoporosis - pathology; Osteoporosis - prevention & control; Ovariectomy; Serum Albumin, Human - chemistry; Serum Albumin, Human - metabolism
• ISSN: 1879-0003

Osteoporosis is a common, age-related disease caused by imbalanced bone remodeling. Current treatments either shut down bone resorption or robustly stimulate bone formation. Here, we describe a novel compound that inhibits osteoclast activity without causing apparent disruptions to bone formation by targeting both c-FMS (i.e., osteoclast differentiation) and αvβ3 integrin (i.e., osteoclastic bone resorption) receptors. We show that human serum albumin (HSA)-conjugated M-CSF protein (M-CSF -HSA) effectively inhibits the activity of both receptors, with a three-fold higher serum half-life compared to the unconjugated M-CSF . We then treated ovariectomized mice with different doses of M-CSF -HSA, alendronate, or a monospecific control protein. The bispecific M-CSF -HSA was superior to a monospecific control in alleviating bone loss and reducing osteoclast distribution and function. M-CSF -HSA and alendronate effectively prevented ovariectomy-induced bone loss, but M-CSF -HSA had a milder inhibitory effect on osteoclast distribution and activity. Moreover, alendronate halted bone formation, while M-CSF -HSA-treated mice showed an increased level of serum amino-terminal propeptide of type I collagen, a bone formation marker. Our data indicate that the mild reduction in osteoclast activity facilitated by the bispecific M-CSF -HSA allows the maintenance of certain levels of bone formation and may be superior to treatments that induce osteoclast depletion.