The contribution of cross-talk between the cell-surface proteins CD36 and CD47–TSP-1 in osteoclast formation and function

• Published in: The Journal of biological chemistry Vol. 293; no. 39; pp. 15055 - 15069
• Main Authors: Koduru, Srinivas V., Sun, Ben-hua, Walker, Joanne M., Zhu, Meiling, Simpson, Christine, Dhodapkar, Madhav, Insogna, Karl L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.09.2018; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; bone; bone resorption; Bone Resorption - genetics; Bone Resorption - pathology; CD36; CD36 Antigens - chemistry; CD36 Antigens - genetics; CD47; CD47 Antigen - chemistry; CD47 Antigen - genetics; Cell Biology; Female; Hypercalcemia - genetics; Hypercalcemia - pathology; Membrane Proteins - chemistry; Membrane Proteins - genetics; Mice; Mice, Knockout; NG-Nitroarginine Methyl Ester - administration & dosage; Nitric Oxide - biosynthesis; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - chemistry; osteoblast; osteoclast; Osteoclasts - chemistry; Osteoclasts - drug effects; Osteoclasts - metabolism; osteocyte; Osteogenesis - genetics; osteoporosis; parathyroid hormone; Parathyroid Hormone - chemistry; Parathyroid Hormone - genetics; Signal Detection, Psychological; Signal Transduction - drug effects; thrombospondin; Thrombospondin 1 - chemistry; Thrombospondin 1 - genetics; TSP-1; thrombospondin; parathyroid hormone; TSP-1; bone resorption; bone; osteoblast; osteocyte; CD36; CD47; osteoclast; osteoporosis
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA117.000633

Antibody-mediated blockade of cluster of differentiation 47 (CD47)–thrombospondin-1 (TSP-1) interactions blocks osteoclast formation in vitro and attenuates parathyroid hormone (PTH)-induced hypercalcemia in vivo in mice. Hypercalcemia in this model reflects increased bone resorption. TSP-1 has two cell-associated binding partners, CD47 and CD36. The roles of these two molecules in mediating the effects of TSP1 in osteoclasts are unclear. Osteoclast formation was attenuated but not absent when preosteoclasts isolated from CD47−/− mice were cocultured with WT osteoblasts. Suppressing CD36 in osteoclast progenitors also attenuated osteoclast formation. The hypercalcemic response to a PTH infusion was blunted in CD47−/−/CD36−/− (double knockout (DKO)) female mice but not CD47−/− mice or CD36−/− animals, supporting a role for both CD47 and CD36 in mediating this effect. Consistent with this, DKO osteoclasts had impaired resorptive activity when analyzed in vitro. Inhibition of nitric oxide (NO) signaling is known to promote osteoclastogenesis, and TSP-1 suppresses NO production and signaling. An anti-TSP-1 antibody increased NO production in osteoclasts, and the inhibitory effect of anti-TSP-1 on osteoclastogenesis was completely rescued by l-nitroarginine methyl ester (l-NAME), a competitive NO synthase inhibitor. Supportive of an important role for CD36 in mediating the pro-osteoclastogenic effects of TSP-1, engaging CD36 with a synthetic agonist, p907, suppressed NO production in anti-TSP-1–treated cultures, allowing osteoclast maturation to occur. These results establish that CD36 and CD47 both participate in mediating the actions of TSP-1 in osteoclasts and establish a physiologically relevant cross-talk in bone tissue between these two molecules.