Blockade of CD26 Signaling Inhibits Human Osteoclast Development

Abstract

Bone remodeling is maintained by the delicate balance between osteoblasts (OBs) and osteoclasts (OCs). However, the role of CD26 in regulating bone remodeling has not yet been characterized. We herein show that CD26 is preferentially expressed on normal human OCs and is intensely expressed on activated human OCs in osteolytic bone alterations. Macrophage-colony stimulating factor (M-CSF) and soluble receptor activator of NF-kB ligand (sRANKL) induced human OC differentiation, in association with CD26 expression on monocyte-macrophage lineage cells. CD26 expression was accompanied by increased phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), which is crucial for early human OC differentiation. The humanized anti-CD26 monoclonal antibody, huCD26mAb, impaired the formation and function of tartrate-resistant acid phosphatase (TRAP)/CD26 positive multi-nucleated (nuclei > 3) OCs with maturation in the manner of dose-dependency. It was revealed that huCD26mAb inhibits early OC differentiation via the inactivation of MKK3/6, p38 MAPK and subsequent dephosphorylation of microphthalmia-associated transcription factor (mi/Mitf). These inhibitions occur immediately after RANKL binds to RANK on the human OC precursor cells and were demonstrated using the OC functional assays. huCD26mAb subsequently impaired OC maturation and bone resorption by suppressing the expression of TRAP and OC fusion proteins. In addition, p38 MAPK inhibitor also strongly inhibited OC formation and function. Our results suggest that the blockade of CD26 signaling impairs the development of human functional OCs by inhibiting p38 MAPK-mi/Mitf phosphorylation pathway and that targeting human OCs with huCD26mAb may have therapeutic potential for the treatment of osteolytic lesions following metastasis to alleviate bone destruction and reduce total skeletal-related events (SREs).

Identification of osteoclast-osteoblast coupling factors in humans reveals links between bone and energy metabolism

“…Soluble DPP4 levels have previously been demonstrated to be increased in postmenopausal women, consistent temporally with the higher rates of bone remodeling that occur following menopause 25 . In agreement with our findings, a previous report demonstrated expression of the membrane-bound form of DPP4, CD26, on osteoclasts in human bone in normal and pathological conditions 29 . As DPP4 is a peptidase targeting glycine/proline sequences, it is possible that osteoclast-derived DPP4 contributes to the degradation of collagen 30 .…”

“…As DPP4 is a peptidase targeting glycine/proline sequences, it is possible that osteoclast-derived DPP4 contributes to the degradation of collagen 30 . However, inhibition of the membrane-bound form of DPP4 appeared to inhibit osteoclast differentiation in vitro without affecting osteoclast resorptive activity 29 . Treatment of osteoblast cultures or mice with DPP4 inhibitors improved osteogenic differentiation and fracture healing 31 .…”

Protective Effects of Vildagliptin against Pioglitazone-Induced Bone Loss in Type 2 Diabetic Rats

“…DPP4 is also known Cluster of differentiation 26 (CD 26). Recent study showed that inhibition of CD 26 signaling inhibited human osteoclast development and humanized anti-CD26 monoclonal antibody may have therapeutic potential for the treatment of osteolytic lesions [33]. Recently some studies reported that DPP4i had anti-inflammatory effects and it also becomes the another possibility [34,35].…”

Effect of Dipeptidyl Peptidase-4 Inhibitors on Bone Metabolism and the Possible Underlying Mechanisms

“…Research suggests that the blockade of CD26 (DPP-4) signaling inhibits the p38 MAPK phosphorylation pathway, which is known to be an important step in early human osteoclast differentiation, and consequently impairs the development of human functional osteoclasts (Nishida et al, 2012, 2014). However, researchers examined the efficacy of thevidagliptin and found no significant inhibitory effect on human osteoclast differentiation or maturation.…”