PTH1R translocation to primary cilia in mechanically‐stimulated ostecytes prevents osteoclast formation via regulation of CXCL5 and IL‐6 secretion

Abstract

Osteocytes respond to mechanical forces controlling osteoblast and osteoclast function. Mechanical stimulation decreases osteocyte apoptosis and promotes bone formation. Primary cilia have been described as potential mechanosensors in bone cells. Certain osteogenic responses induced by fluid flow (FF) in vitro are decreased by primary cilia inhibition in MLO‐Y4 osteocytes. The parathyroid hormone (PTH) receptor type 1 (PTH1R) modulates osteoblast, osteoclast, and osteocyte effects upon activation by PTH or PTH‐related protein (PTHrP) in osteoblastic cells. Moreover, some actions of PTH1R seem to be triggered directly by mechanical stimulation. We hypothesize that PTH1R forms a signaling complex in the primary cilium that is essential for mechanotransduction in osteocytes and affects osteocyte‐osteoclast communication. MLO‐Y4 osteocytes were stimulated by FF or PTHrP (1−37). PTH1R and primary cilia signaling were abrogated using PTH1R or primary cilia specific siRNAs or inhibitors, respectively. Conditioned media obtained from mechanically‐ or PTHrP‐stimulated MLO‐Y4 cells inhibited the migration of preosteoclastic cells and osteoclast differentiation. Redistribution of PTH1R along the entire cilium was observed in mechanically stimulated MLO‐Y4 osteocytic cells. Preincubation of MLO‐Y4 cells with the Gli‐1 antagonist, the adenylate cyclase inhibitor (SQ22536), or with the phospholipase C inhibitor (U73122), affected the migration of osteoclast precursors and osteoclastogenesis. Proteomic analysis and neutralizing experiments showed that FF and PTH1R activation control osteoclast function through the modulation of C‐X‐C Motif Chemokine Ligand 5 (CXCL5) and interleukin‐6 (IL‐6) secretion in osteocytes. These novel findings indicate that both primary cilium and PTH1R are necessary in osteocytes for proper communication with osteoclasts and show that mechanical stimulation inhibits osteoclast recruitment and differentiation through CXCL5, while PTH1R activation regulate these processes via IL‐6.

Recent advances in primary cilia in bone metabolism

“…Parathyroid hormone (PTH) receptor 1 (PTH1R) is a B-group G protein-coupled receptor (GPCR), which plays an important role in bone metabolism, and activation of PTH1R was found to regulate osteoclasts. Tirado-Cabrera ( 62 ) reported the localization of PTH1R to primary cilia, which confirmed that primary cilia in osteoblasts are necessary for proper communication with osteoclasts.IL-6 secretion is increased when PTH1R is silenced. Previous studies have shown that IL-6 enhances osteoblast-mediated osteoclastogenesis by promoting the activities of JAK2 and RANKL ( 63 ).…”

Significance of mechanical loading in bone fracture healing, bone regeneration, and vascularization

“…157,158 Osteocytes with PTH1R translocation to primary cilia can prevent osteoclast formation under FSS by manipulating CXCL5 and IL-6 secretion. 159 Therefore, restoring or enhancing the function of primary cilia may be a potential strategy to combat bone loss associated with mechanical disuse, such as microgravity. Nevertheless, current studies do not support the existence of primary cilia in osteoclasts.…”

Programmed cell death of periodontal ligament cells

“…In addition, compressive stress can also stimulate angiogenesis, which is essential for osteoclast generation and represents a potential mechanism underlying the remodeling of periodontal bone (Wang, Zheng, et al, 2022). However, The parathyroid hormone receptor type 1 is translocated to primary cilia in mechanically stimulated bone cells, preventing the formation of osteoclasts by regulating the secretion of CXCL5 and IL‐6, suggesting that mechanical stress also inhibits osteoclast recruitment and differentiation (Tirado‐Cabrera et al, 2022).…”