Osteocyte necrosis triggers osteoclast-mediated bone loss through macrophage-inducible C-type lectin

Andreev, Darja; Liu, Mengdan; Weidner, Daniela; Kachler, Katerina; Faas, Maria M.; Grüneboom, Anika; Schlötzer‐Schrehardt, Ursula; Muñoz, Luis; Steffen, Ulrike; Grötsch, Bettina; Killy, Barbara; Krönke, Gerhard; Luebke, Andreas M.; Niemeier, Andreas; Wehrhan, Falk; Lang, Roland; Schett, Georg; Bözec, Aline

doi:10.1172/jci134214

Cited by 112 publications

(89 citation statements)

References 66 publications

(73 reference statements)

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“…This interpretation is somehow nihilistic as it puts the secretome in the light of catabolism, but accumulating evidence greatly supports a positive view on the secretome with respect to myocarditis [ 19 ], chronic heart failure [ 20 ], spinal cord injury [ 21 ], stroke [ 22 ], and wound healing [ 23 ]. Thus, we have to appreciate the paradigm that dying blood-born mononuclear cells, maybe in concert with the dying osteocytes [ 6 ], signal the need for bone removal before the anabolic process of renewal is initiated. In support of this paradigm, the secretome is stimulating angiogenesis [ 31 ], and angiogenesis is critically involved in bone regeneration [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, conditional deletion of TGF-β receptor signaling in osteoclast progenitors would help to test this hypothesis. Recent observations that necrotic osteocytes release spliceosome-associated protein 130, a macrophage-inducible C-type lectin ligand pushing osteoclastogenesis [ 6 ], may provide another molecular mechanism linking the secretome of dying cells with osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Imbalanced bone remodeling, as well as inflammatory osteolysis, are both controlled by paracrine signals, including those originating from dying cells. It is particularly the apoptotic [ 5 , 6 ], senescent [ 7 ], and necrotic osteocytes [ 6 ] that signal the need to resorb the damaged bone areas that might be infected by oral pathogens, for instance, in periodontitis. This mechanism of controlling local osteoclastogenesis is not restricted to osteocytes as also senescent fibroblasts can drive the process of osteoclastogenesis [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

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TGF-β in the Secretome of Irradiated Peripheral Blood Mononuclear Cells Supports In Vitro Osteoclastogenesis

Panahipour

Kargarpour

Laggner

et al. 2020

IJMS

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Osteoclastogenesis required for bone remodeling is also a key pathologic mechanism of inflammatory osteolysis being controlled by paracrine factors released from dying cells. The secretome of irradiated, dying peripheral blood mononuclear cells (PBMCs) has a major impact on the differentiation of myeloid cells into dendritic cells, and macrophage polarization. The impact on osteoclastogenesis, however, has not been reported. For this aim, we used murine bone marrow macrophages exposed to RANKL and M-CSF to initiate osteoclastogenesis, with and without the secretome obtained from γ-irradiated PBMCs. We reported that the secretome significantly enhanced in vitro osteoclastogenesis as determined by means of histochemical staining of the tartrate-resistant acid phosphatase (TRAP), as well as the expression of the respective target genes, including TRAP and cathepsin K. Considering that TGF-β enhanced osteoclastogenesis, we confirmed the TGF-β activity in the secretome with a bioassay that was based on the increased expression of IL11 in fibroblasts. Neutralizing TGF-β by an antibody decreased the ability of the secretome to support osteoclastogenesis. These findings suggested that TGF-β released by irradiated PBMCs could enhance the process of osteoclastogenesis in vitro.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

TGF-β in the Secretome of Irradiated Peripheral Blood Mononuclear Cells Supports In Vitro Osteoclastogenesis

Panahipour

Kargarpour

Laggner

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Upon damage, osteocytes might release damage-associated molecular patterns (DAMPs), which then activated osteoclasts through Mincle, a DAMP sensor. In this way, osteoclasts could sense osteocyte necrosis and initiate bone resorption independent of the sclerostin-RANKL pathway [ 102 ]. Hence, osteocyte death induced by overload or microfracture might explain the thinning of the subchondral bone in early-stage OA and the uncoupled osteoblastic and osteoclastic activities [ 8 ].…”

Section: Osteocyte Dysfunctionmentioning

confidence: 99%

Osteocyte Dysfunction in Joint Homeostasis and Osteoarthritis

Zhang

Wen

2021

IJMS

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Structural disturbances of the subchondral bone are a hallmark of osteoarthritis (OA), including sclerotic changes, cystic lesions, and osteophyte formation. Osteocytes act as mechanosensory units for the micro-cracks in response to mechanical loading. Once stimulated, osteocytes initiate the reparative process by recruiting bone-resorbing cells and bone-forming cells to maintain bone homeostasis. Osteocyte-expressed sclerostin is known as a negative regulator of bone formation through Wnt signaling and the RANKL pathway. In this review, we will summarize current understandings of osteocytes at the crossroad of allometry and mechanobiology to exploit the relationship between osteocyte morphology and function in the context of joint aging and osteoarthritis. We also aimed to summarize the osteocyte dysfunction and its link with structural and functional disturbances of the osteoarthritic subchondral bone at the molecular level. Compared with normal bones, the osteoarthritic subchondral bone is characterized by a higher bone volume fraction, a larger trabecular bone number in the load-bearing region, and an increase in thickness of pre-existing trabeculae. This may relate to the aberrant expressions of sclerostin, periostin, dentin matrix protein 1, matrix extracellular phosphoglycoprotein, insulin-like growth factor 1, and transforming growth factor-beta, among others. The number of osteocyte lacunae embedded in OA bone is also significantly higher, yet the volume of individual lacuna is relatively smaller, which could suggest abnormal metabolism in association with allometry. The remarkably lower percentage of sclerostin-positive osteocytes, together with clustering of Runx-2 positive pre-osteoblasts, may suggest altered regulation of osteoblast differentiation and osteoblast-osteocyte transformation affected by both signaling molecules and the extracellular matrix. Aberrant osteocyte morphology and function, along with anomalies in molecular signaling mechanisms, might explain in part, if not all, the pre-osteoblast clustering and the uncoupled bone remodeling in OA subchondral bone.

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“…Among multiple cell types, macrophages are in a unique position playing pivotal roles in both processes and may serve as an important target for modulation. [ 19–21 ] On the one hand, excess proinflammatory macrophages prevail under osteoporotic conditions and their activities should be modulated for healing; [ 22,23 ] on the other hand, macrophages play a central role in orchestrating almost all healing processes—particularly including mediating biomaterials implantation and bone repair. [ 24 ] Therefore, the goal to improve the regenerative outcomes should be to activate macrophages at an appropriate stage and into an appropriate phenotype, so as to improve implant‐bone integration while slowing down bone loss during the surgeries in osteoporosis patients.…”

Section: Introductionmentioning

confidence: 99%

Switching On and Off Macrophages by a “Bridge‐Burning” Coating Improves Bone‐Implant Integration under Osteoporosis

Wang

Niu

Tian

et al. 2020

Adv Funct Materials

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Osteoporosis poses substantial challenges for biomaterials implantation. New approaches to improve bone‐implant integration should resolve the fundamental dilemma of inflammation—proper inflammation is required at early stages but should be suppressed later for better healing, especially under osteoporosis. However, precisely switching on and off inflammation around implants in vivo remains unachieved. To address this challenge, a “bridge‐burning” coating material that comprises a macrophage‐activating glycan covalently crosslinked by a macrophage‐eliminating bisphosphonate to titanium implant surface is designed. Upon implantation, the glycan instructs host macrophages to release pro‐osteogenic cytokines (“switch‐on”), promoting bone cell differentiation. Later, increasingly mature bone cells secrete alkaline phosphatase to cleave the glycan‐bisphosphonate complexes from the implant, which in turn selectively kill the proinflammatory macrophages (“switch‐off”) that have completed their contribution—hence in the manner of “burning bridges”—to promote healing. In vivo examination in an osteoporotic rat model demonstrates that this coating significantly enhances bone‐implant integration (88.4% higher contact ratio) through modulating local inflammatory niches. In summary, a bioresponsive, endogenously triggered, smart coating material is developed to sequentially harness and abolish the power of inflammation to improve osseointegration under osteoporosis, which represents a new strategy for designing immunomodulatory biomaterials for tissue regeneration.

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Osteocyte necrosis triggers osteoclast-mediated bone loss through macrophage-inducible C-type lectin

Cited by 112 publications

References 66 publications

TGF-β in the Secretome of Irradiated Peripheral Blood Mononuclear Cells Supports In Vitro Osteoclastogenesis

TGF-β in the Secretome of Irradiated Peripheral Blood Mononuclear Cells Supports In Vitro Osteoclastogenesis

Osteocyte Dysfunction in Joint Homeostasis and Osteoarthritis

Switching On and Off Macrophages by a “Bridge‐Burning” Coating Improves Bone‐Implant Integration under Osteoporosis

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