The novel cytotoxic polybisphosphonate osteodex decreases bone resorption by enhancing cell death of mature osteoclasts without affecting osteoclastogenesis of RANKL-stimulated mouse bone marrow macrophages

• Published in: Investigational new drugs Vol. 42; no. 2; pp. 207 - 220
• Main Authors: Henning, Petra, Westerlund, Anna, Movérare-Skrtic, Sofia, Lindholm, Catharina, Márquez-Méndez, Marcela, Nilsson, Sten, Holmberg, Anders R., Lerner, Ulf H.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-04-2024; Springer Nature B.V
• Subjects: Animals; Bisphosphonates; Bone growth; Bone Marrow; Bone resorption; Bone Resorption - drug therapy; Bone Resorption - metabolism; Cancer and Oncology; Cancer och onkologi; Cell culture; Cell Death; Cell Differentiation; Cells (biology); Cells, Cultured; Cytotoxicity; Differentiation; Gene expression; Macrophages; Macrophages - metabolism; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Mice; Mortality; Oncology; Osteoclastogenesis; Osteoclasts; Osteoclasts - metabolism; Osteodex; Osteogenesis; Osteoprogenitor cells; Osteoprotegerin; Pharmacology/Toxicology; Progenitor cells; RANK Ligand - metabolism; RANK Ligand - pharmacology; RANKL; RNA, Messenger - metabolism; TRANCE protein; Vitamin D3; Zoledronic acid; Zoledronic Acid - metabolism; Zoledronic Acid - pharmacology; Osteoclasts; RANKL; Osteodex; Bisphosphonates
• ISSN: 0167-6997; 1573-0646; 1573-0646
• DOI: 10.1007/s10637-024-01427-1

Summary
It has previously been demonstrated that the polybisphosphonate osteodex (ODX) inhibits bone resorption in organ-cultured mouse calvarial bone. In this study, we further investigate the effects by ODX on osteoclast differentiation, formation, and function in several different bone organ and cell cultures. Zoledronic acid (ZOL) was used for comparison. In retinoid-stimulated mouse calvarial organ cultures, ODX and ZOL significantly reduced the numbers of periosteal osteoclasts without affecting
Tnfsf11
or
Tnfrsf11b
mRNA expression. ODX and ZOL also drastically reduced the numbers of osteoclasts in cell cultures isolated from the calvarial bone and in vitamin D3–stimulated mouse crude bone marrow cell cultures. These data suggest that ODX can inhibit osteoclast formation by inhibiting the differentiation of osteoclast progenitor cells or by directly targeting mature osteoclasts. We therefore assessed if osteoclast formation in purified bone marrow macrophage cultures stimulated by RANKL was inhibited by ODX and ZOL and found that the initial formation of mature osteoclasts was not affected, but that the bisphosphonates enhanced cell death of mature osteoclasts. In agreement with these findings, ODX and ZOL did not affect the mRNA expression of the osteoclastic genes
Acp5
and
Ctsk
and the osteoclastogenic transcription factor
Nfatc1
. When bone marrow macrophages were incubated on bone slices, ODX and ZOL inhibited RANKL-stimulated bone resorption. In conclusion, ODX does not inhibit osteoclast formation but inhibits osteoclastic bone resorption by decreasing osteoclast numbers through enhanced cell death of mature osteoclasts.