Osteoclast-osteoblast Communication Research Articles

Therapeutic Effect of Calcimimetics on Osteoclast-Osteoblast Crosslink in Chronic Kidney Disease and Mineral Bone Disease.

We have previously demonstrated calcimimetics optimize the balance between osteoclastic bone resorption and osteoblastic mineralization through upregulating Wingless and int-1 (Wnt) signaling pathways in the mouse and cell model. Nonetheless, definitive human data are unavailable concerning therapeutic effects of Cinacalcet on chronic kidney disease and mineral bone disease (CKD-MBD) and osteoclast–osteoblast interaction. We aim to investigate whether Cinacalcet therapy improves bone mineral density (BMD) through optimizing osteocytic homeostasis in a human model. Hemodialysis patients with persistently high intact parathyroid hormone (iPTH) levels > 300 pg/mL for more than 3 months were included and received fixed dose Cinacalcet (25 mg/day, orally) for 6 months. Bone markers presenting osteoclast–osteoblast communication were evaluated at baseline, the 3rd and the 6th month. Eighty percent of study patients were responding to Cinacalcet treatment, capable of improving BMD, T score and Z score (16.4%, 20.7% and 11.1%, respectively). A significant correlation between BMD improvement and iPTH changes was noted (r = −0.26, p < 0.01). Nonetheless, baseline lower iPTH level was associated with better responsiveness to Cinacalcet therapy. Sclerostin, an inhibitor of canonical Wnt/β-catenin signaling, was decreased from 127.3 ± 102.3 pg/mL to 57.9 ± 33.6 pg/mL. Furthermore, Wnt-10b/Wnt 16 expressions were increased from 12.4 ± 24.2/166.6 ± 73.3 pg/mL to 33.8 ± 2.1/217.3 ± 62.6 pg/mL. Notably, procollagen type I amino-terminal propeptide (PINP), a marker of bone formation and osteoblastic activity, was increased from baseline 0.9 ± 0.4 pg/mL to 91.4 ± 42.3 pg/mL. In contrast, tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), a marker of osteoclast activity, was decreased from baseline 16.5 ± 0.4 mIU/mL to 7.7 ± 2.2 mIU/mL. Moreover, C-reactive protein levels were suppressed from 2.5 ± 0.6 to 0.8 ± 0.5 mg/L, suggesting the systemic inflammatory burden may be benefited after optimizing the parathyroid–bone axis. In conclusion, beyond iPTH suppression, our human model suggests Cinacalcet intensifies BMD through inhibiting sclerostin expression and upregulating Wnt-10b/Wnt 16 signaling that activates osteoblastic bone formation and inhibits osteoclastic bone resorption and inflammation. From the perspective of translation to humans, this research trial brings a meaningful insight into the osteoblast–osteoclast homeostasis in Cinacalcet therapy for CKD-MBD.

Bone Cell Communication Factors Provide a New Therapeutic Strategy for Osteoporosis.

Bone homeostasis is strictly regulated by the balance between bone resorption by osteoclasts and bone formation by osteoblasts. Many studies have shown that osteoclasts affect osteoblasts, and vice versa, through diffusible paracrine factors, cell-cell contact, and cell-bone matrix interactions to achieve the correct balance between osteoclastic and osteoblastic activities in the basic multicellular unit (BMU). The strict regulation that occurs during bone remodeling hinders the long-term use of the currently available antiresorptive agents and anabolic agents for the treatment of osteoporosis. To overcome these limitations, it is necessary to develop novel agents that simultaneously inhibit bone resorption, promote bone formation, and decouple resorption from formation. Therefore, a more detailed understanding of the mechanisms involved in osteoclast-osteoblast communication during bone remodeling is necessary.

Osteoclast-derived exosomes inhibit osteogenic differentiation through Wnt/β-catenin signaling pathway in simulated microgravity model

In the microgravity environment of space, astronauts undergo osteoporosis due to an imbalance in bone remodeling. Recent studies have shown that exosomes derived from osteoclasts could mediate cell-to-cell communication in bone remodeling. However, the role of osteoclast-derived exosomes in bone remodeling in microgravity remains a mystery. Our objective is to investigate the cellular processes modulated by exosomes from RAW264.7 cell-derived osteoclasts and the underlying mechanism of action for the exosomes-mediated osteogenesis of osteoblast-like MC3T3-E1 cells in simulated microgravity. We took advantage of the random positioning machine (RPM) to simulate microgravity for the model and investigated the role of exosomes from RAW264.7 cell-derived osteoclasts in osteoclast-osteoblast communication. The results showed that this type of mature osteoclast-derived exosomes (OC-Exos) in the RPM evidently inhibited the cellular proliferation of osteoblasts via inducing cellular apoptosis and altering their cell cycle distribution. Alkaline phosphatase and mineralization activity of MC3T3-E1 cells were significantly lower after treatment with OC-Exos from RPM and mRNA expression of osteoblast-specific genes were down-regulated. Further study confirmed that OC-Exos in RPM obstructed the differentiation of MC3T3-E1 cells by interfering with Wnt/β-catenin signaling pathway. Together, these observations demonstrated that OC-Exos played an essential role in the regulation of bone remodeling in the microgravity environment. These results shed light on a novel pathway of cross-talk between osteoclasts and osteoblasts, which will be helpful to explain the possible mechanisms underlying osteoporosis in microgravity.

Osteoclast-Derived Extracellular Vesicles: Novel Regulators of Osteoclastogenesis and Osteoclast-Osteoblasts Communication in Bone Remodeling.

Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, play an important role in cellular communication during skeletal growth and homeostasis. Bioactive molecules carried by EVs are transported to neighboring and distant cells to trigger a series of signaling cascades influencing bone homeostasis. The bioactive activities of osteoclast-derived EVs include regulation of osteoclastogenesis and osteoclast–osteoblast communication. As osteoclast-derived EVs have the potential to regulate osteoclasts and osteoblasts, their application in osteoporosis and other bone metabolic disorders is currently under investigation. However, very few reviews of osteoclast-derived EVs in bone remodeling regulation have yet been published. This article aims to review recent advances in this field, summarizing a new regulator of osteoclastogenesis and osteoclast–osteoblast communication mediated by osteoclast-derived EVs. We will analyze the major challenges in the field and potential for the therapeutic application of EVs.

BMP Signaling Mediated by BMPR1A in Osteoclasts Negatively Regulates Osteoblast Mineralization Through Suppression of Cx43.

Osteoblasts and osteoclasts are well orchestrated through different mechanisms of communication during bone remodeling. Previously, we found that osteoclast-specific disruption of one of the BMP receptors, Bmpr1a, results in increased osteoblastic bone formation in mice. We hypothesized that BMPR1A signaling in osteoclasts regulates production of either membrane bound proteins or secreted molecules that regulated osteoblast differentiation. In our current study, we co-cultured wild-type osteoblasts with either control osteoclasts or osteoclasts lacking BMPR1A signaling activity. We found that loss of Bmpr1a in osteoclasts promoted osteoblast mineralization in vitro. Further, we found that the expression of Cx43/Gja1 in the mutant osteoclasts was increased, which encoded for one of the gap junction proteins connexin 43/gap junction alpha 1. Knockdown of Gja1 in the mutant osteoclasts for Bmpr1a reduced osteoblastic mineralization when co-cultured. Our findings suggest that GJA1 may be one of the downstream targets of BMPR1A signaling in osteoclasts that mediates osteoclast-osteoblast communication during bone remodeling. J. Cell. Biochem. 118: 605-614, 2017. © 2016 Wiley Periodicals, Inc.

Communication Factors-Promising Targets in Osteoporosis Treatment

Osteoporosis is one of the most serious under-diagnosed and under-treated recessive diseases, leading to increased mortality and morbidity as well as huge economic burden. The fundamental reason for the occurrence of osteoporosis lies in the disequilibrium between bone resorption mediated by osteoclasts and bone formation mediated by osteoblasts. Osteoclast-osteoblast communication plays important roles in the maintenance of hemeostasis. In this review, we present the detailed mechanisms of this communication, including modes of diffusible paracrine factors, cell-cell direct contact and cell-bone matrix interaction. We demonstrate that osteoclasts (or osteoblasts) could not only secrete cytokines, growth factors, chemokines and function in a paracrine manner, but also express molecules on their membranes to bind to the receptors on osteoblasts (or osteoclasts) to transduce bidirectional signals. Moreover, growth factors and cytokines deliberated from bone matrix during bone resorption could also regulate the function of both osteoblasts and osteoclasts. This review gives the latest knowledge of communication factors, some of which are emerging as novel therapeutic targets for future development of antiosteoporotic drugs.

Osteoblast and Osteoclast Crosstalks: From OAF to Ephrin

The maintenance of bone homeostasis is tightly controlled, and largely dependent upon cellular communication between osteoclasts and osteoblasts, and the coupling of bone resorption to bone formation. This tight coupling is essential for the correct function and maintenance of the skeletal system, repairing microscopic skeletal damage and replacing aged bone. Cells in osteoclast and osteoblast lineages communicate with each other through diffusible paracrine factors, cell-cell contact, and cell-bone matrix interaction. Osteoclast-osteoblast communication occurs in a basic multicellular unit (BMU) at the initiation, transition and termination phases of bone remodeling. At the initiation phase, hematopoietic precursors are recruited to the BMU. These precursors differentiate into osteoclasts following interactions with osteoblasts, which express and/or secrete ligands as RANK-L and OPG. Subsequently, the transition from bone resorption to formation is mediated by osteoclast-derived 'coupling factors', which direct the differentiation and activation of osteoblasts in resorbed lacunae to refill it with new bone. Signals derived from molecules released from the resorbed bone matrix, as TGF-beta and bidirectional signaling generated by interaction between ephrinB2 on osteoclasts and EphB4 on osteoblast precursors facilitates the transition. At the termination phase, bone remodeling is completed by osteoblastic bone formation and mineralization of bone matrix. The research steps that brought to the present knowledge are summarized in this review.

Cross-talk among bone cells

Bone cells such as osteoclasts, osteoblasts, and osteocytes 'talk' to each other throughout adult life to maintain bone integrity. This review highlights frontier areas of research on intercellular communication among bone cells. Bone cells communicate to regulate the balance between bone resorption and bone formation. Recent findings have suggested that bone remodeling compartment is critical for osteoclast-osteoblast communication during bone remodeling. New molecules and mechanisms for bone cell communication, including 'coupling' of bone formation to resorption, have been revealed. Osteoclastic regulation of pH within the bone remodeling compartment is a mechanism that has been posited to rapidly activate osteoblastic bone formation, whereas osteocytes in the bone matrix regulate osteoclasts and osteoblasts on the bone surface through the lacuno-canaliculi network. Differentiation, activation, and apoptosis of bone cells are often dependent on the status of other types of bone cells. Bone cells in different lineages achieve intercellular communication not only by ligand-receptor interactions but also by molecules and ions traveling in the extracellular space or across gap junctions, processes that depend profoundly on the four-dimensional (space and time) architecture of bone tissue.

Biomechanical effects of the full range of useful doses of (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) on femur diaphyses and cortical bone tissue in rats

The effects of i.p. doses of 0.016, 0.16, 1.6, 5, 16, 50 and 160 μM/kg/day of APD, over a period of 23 days, on geometric and biomechanical properties of femoral diaphyses in bending were determined in groups of seven growing rats. Both elastic and ultimate strength increased with low doses and decreased with high doses. Geometric (mass) variables (diaphyseal volume, wall/lumen ratio) correlated positively, and material properties (limit elastic stress, modulus of elasticity) negatively, with log dose. Normal mass and improved quality at low doses, and improved mass and impaired quality data at high doses were obtained. No changes in sectional moment of inertia ( Ix, an expression of bone architecture) were observed. Biphasic changes in diaphyseal strength expressed the effects of APD on material quality in spite of mass variation. The contrasting lack of changes in Ix may have reflected the blocking effect of APD on osteoclast-osteoblast communication, essential for directional modulation of remodelling.