A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and [alpha].sub.v[beta].sub.3 integrin for osteoporosis therapy
Author(s): Yuval Zur 1, Lior Rosenfeld 1, Chen Anna Keshelman 2, Nofar Dalal 1, Gali Guterman-Ram 3, Ayelet Orenbuch 3, Yulia Einav 4, Noam Levaot 3,*, Niv Papo 1,*
Osteoporosis, a chronic skeletal disorder common in both women and men beyond the age of 50 , is the underlying cause of more than 8.9 million fractures annually worldwide, with the consequent high burden of social and economic costs . The drugs initially used for the management of osteoporosis in women were based on estrogens, but long-term administration of these drugs is associated with increased risk of breast cancer, cardiovascular disease, and dementia [3-5]. To date, the most commonly prescribed drugs for osteoporosis are bisphosphonates, but these drugs, too, have nonspecific adverse side effects, such as gastrointestinal toxicity, renal toxicity, hypercalcemia, osteonecrosis of the jaw, and more . A different therapeutic direction was recently opened with the Food and Drug Administration (FDA) approval of the receptor for activation of the nuclear factor-kappa B (NF-ÐºB) ligand (RANKL) antibody, denosumab, but the clinical promise of this drug has been offset by reports of adverse side effects, such as hypocalcemia  and atypical hip fractures . Thus, there is a pressing need for new efficient and highly specific drugs for the management of osteoporosis.
Central to the pathogenesis of osteoporosis is excessive bone resorption by osteoclasts . These cells differentiate from cells of the monocyte/macrophage lineage upon stimulation of two essential factors, monocyte/macrophage colony-stimulating factor (M-CSF) and RANKL . The importance of M-CSF and its receptor c-FMS in osteoclast function has been clearly illustrated in a study showing that both M-CSF-deficient and c-FMS-deficient mice suffer from retarded skeletal growth and osteopetrosis . Another factor that is essential for osteoclast functioning is [alpha] v [beta]3 integrin, as indicated, for example, in studies showing increased bone mass in integrin [beta]3 knockout mice due to a functional defect in their osteoclasts [12-15]. The interaction of [alpha]v [beta]3 integrin with the bone matrix induces a cytoskeleton organization that polarizes the osteoclast's resorptive machinery to the bone/cell interface, where it creates an isolated compartment consisting of an actin ring surrounding a ruffled border essential for resorption by the matured osteoclasts.
Importantly, in addition to the distinctive roles of c-FMS and [alpha] v [beta]3 integrin in osteoclast activity, these two factors also play a cooperative role in bone resorption. M-CSF signaling regulates bone resorption by crosstalk through its receptor c-FMS, with the signaling being activated by [alpha]v [beta]3 integrin. This signaling regulates cytoskeleton rearrangement, as both M-CSF and [alpha]v [beta]3 integrin stimulate the same c-Src-initiated signaling complex essential for regulation of the osteoclast cytoskeleton [16-18]. In addition, c-FMS alters the conformation of [alpha]v [beta]3 integrin from a low-affinity to a high-affinity state , and it activates the Rho GTPase family member Rac (which is essential for osteoclast cytoskeleton organization) in an [alpha]v [beta]3 -integrin-dependent manner [16,20]. Moreover, it has been demonstrated that [beta]3 -integrin-deficient mice...
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