PTPRJ promotes osteoclast maturation and activity by inhibiting Cbl‐mediated ubiquitination of NFATc1 in late osteoclastogenesis

Abstract

Bone‐resorbing osteoclasts (OCLs) are multinucleated phagocytes, whose central roles in regulating bone formation and homeostasis are critical for normal health and development. OCLs are produced from precursor monocytes in a multistage process that includes initial differentiation, cell–cell fusion, and subsequent functional and morphological maturation; the molecular regulation of osteoclastogenesis is not fully understood. Here, we identify the receptor‐type protein tyrosine phosphatase PTPRJ as an essential regulator specifically of OCL maturation. Monocytes from PTPRJ‐deficient (JKO) mice differentiate and fuse normally, but their maturation into functional OCLs and their ability to degrade bone are severely inhibited. In agreement, mice lacking PTPRJ throughout their bodies or only in OCLs exhibit increased bone mass due to reduced OCL‐mediated bone resorption. We further show that PTPRJ promotes OCL maturation by dephosphorylating the M‐CSF receptor (M‐CSFR) and Cbl, thus reducing the ubiquitination and degradation of the key osteoclastogenic transcription factor NFATc1. Loss of PTPRJ increases ubiquitination of NFATc1 and reduces its amounts at later stages of osteoclastogenesis, thereby inhibiting OCL maturation. PTPRJ thus fulfills an essential and cell‐autonomous role in promoting OCL maturation by balancing between the pro‐ and anti‐osteoclastogenic activities of the M‐CSFR and maintaining NFATc1 expression during late osteoclastogenesis.

Recent advances of NFATc1 in rheumatoid arthritis-related bone destruction: mechanisms and potential therapeutic targets

“…Shalev et al discovered that protein tyrosine phosphatase receptor type J (PTPRJ) promotes osteoclast differentiation by decreasing ubiquitination and degradation of the key osteoclast transcription factor NFATc1 through dephosphorylation of M-CSF receptor (M-CSFR) and Cbl. The deletion of PTPRJ increases the ubiquitination of NFATc1 and decreases its expression, thereby inhibiting femoral cell maturation (Shalev et al 2021 ). Narahara et al found that Kelch repeat and BTB domain-containing protein 11 (KBTBD11) interacts with the E3 ubiquitin ligase Cullin3, promoting the ubiquitination and degradation of NFATc1 by the proteasome.…”

The role of E3 ubiquitin ligases in bone homeostasis and related diseases

“…As another RING-finger type E3 ligase, Cullin3 recognizes NFATC1 via combining the protein tyrosine phosphatase domain of Kelch repeat and BTB domain-containing protein 11, the specific adaptor of Cullin3 and deficiency of which also favors OCs functions 85 . One recent work reported that OCs maturation is benefited from inhibition of interaction between CBL and NFATC1 86 .…”