Progranulin is essential for bone homeostasis and immunology

Abstract

Intercellular communication or crosstalk between immune and skeletal cells is considered a crucial element in bone homeostasis modulation. Progranulin (PGRN) is an autocrine growth factor that is structured as beads‐on‐a‐string and participates in multiple pathophysiological processes, including atherosclerosis, arthritis, neurodegenerative pathologies, cancer, and wound repair. PGRN functions as a competitor that binds to tumor necrosis factor receptor 1 (TNFR1), thereby blocking the TNF‐α pathway. PGRN is regarded as an agonist of chondrogenesis and osteogenesis, delaying the progression of inflammation through the TNFR2 pathway. The exploitation of PGRN may bring benefits for inflammatory bone diseases and the stabilization of bone homeostasis. The PGRN‐modified analog Atsttrin possesses three TNFR‐binding fragments and thereby exerts superior therapeutic effects on multiple preclinical animal models compared to PGRN. In this review, we highlight the emerging roles of PGRN in bone formation, as well as in physiological and TNF‐α–mediated inflammatory conditions revealed in recent discoveries. We address potential therapies for the treatment of inflammatory bone conditions, such as periodontitis, by the use of PGRN and its derivative Atsttrin.

Atsttrin regulates osteoblastogenesis and osteoclastogenesis through the TNFR pathway

“…Atsttrin and PGRN have similar physiological functions and can also bind to TNFR and inhibit TNF-α signaling pathways 20 , 21 . Moreover, Atsttrin showed longer half-lives and stronger therapeutic effects in previous studies compared to PGRN 21 – 23 . At the same time, we found that Atsttrin plays an important role in protecting early inflammatory arthritis in animal models and promoting cartilage repair 20 , 21 .…”

Enhanced immunomodulation and periodontal regeneration efficacy of subgingivally delivered progranulin‐loaded hydrogel as an adjunct to non‐surgical treatment for Class II furcation involvement in dogs

“…Moreover, in the PGRN‐knockout mice, PGRN was essential for maintaining bone mass by inhibiting TNF‐α‐induced osteoclastogenesis and promoting osteoblastogenesis (Noguchi et al, 2015). A recent review has also comprehensively summarized the active role of PGRN in bone homeostasis (Chen et al, 2022). In brief, our findings are consistent with those of the above studies, indicating that PGRN could also promote periodontal regeneration under non‐surgical conditions.…”

“…In addition, PGRN can exert its immunomodulatory effects by inhibiting M1 macrophage polarization and Th17 cell differentiation and by promoting M2 macrophage polarization and Treg cell differentiation (Chen, Wang, et al, 2020; Wang et al, 2022). PGRN also plays a crucial role in maintaining bone homeostasis, particularly in the context of inflammation (Chen et al, 2022). Our research group has evaluated the function and application potential of PGRN in periodontitis in many aspects (Chen et al, 2019; Chen, Yu, et al, 2020; Li et al, 2018; Liu et al, 2020).…”