Inhibition of Sca-1-Positive Skeletal Stem Cell Recruitment by Alendronate Blunts the Anabolic Effects of Parathyroid Hormone on Bone Remodeling

Wu, Xiangwei; Pang, Lijuan; Lei, Weiqi; Lu, William W.; Jun, Li; Li, Zhaoyang; Frassica, Frank J.; Chen, Xueling; Wan, Mei; Cao, Xu

doi:10.1016/j.stem.2010.09.012

Cited by 119 publications

(104 citation statements)

References 42 publications

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“…Alendronate, a potent inhibitor of bone turnover, is widely used for treatment of high-turnover bone disease, such as postmenopausal osteoporosis. However, it has been recognized clinically that inhibition of osteoclastic function by alendronate blunts the anabolic action of PTH (4), and the underlying mechanism is beginning to be understood (21). We found that along with a reduction in bone turnover markers after treatment with alendronate (Supplemental Figure 8), Cthrc1 expression in bone was substantially reduced, in contrast to the increased expression of Ctsk and Calcr ( Figure 8B).…”

Section: Coupling Function In Vivomentioning

confidence: 69%

Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation

Takeshita¹,

Fumoto²,

Matsuoka³

et al. 2013

J. Clin. Invest.

199

179

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Bone remodeling is characterized by the sequential, local tethering of osteoclasts and osteoblasts and is key to the maintenance of bone integrity. While bone matrix-mobilized growth factors, such as TGF-β, are proposed to regulate remodeling, no in vivo evidence exists that an osteoclast-produced molecule serves as a coupling factor for bone resorption to formation. We found that CTHRC1, a protein secreted by mature boneresorbing osteoclasts, targets stromal cells to stimulate osteogenesis. Cthrc1 expression was robustly induced when mature osteoclasts were placed on dentin or hydroxyapatite, and also by increasing extracellular calcium. Cthrc1 expression in bone increased in a high-turnover state (such as that induced by RANKL injections in vivo), but decreased in conditions associated with suppressed bone turnover (such as with aging and after alendronate treatment). Targeted deletion of Cthrc1 in mice eliminated Cthrc1 expression in bone, whereas its deficiency in osteoblasts did not exert any significant effect. Osteoclast-specific deletion of Cthrc1 resulted in osteopenia due to reduced bone formation and impaired the coupling process after resorption induced by RANKL injections, impairing bone mass recovery. These data demonstrate that CTHRC1 is an osteoclastsecreted coupling factor that regulates bone remodeling. IntroductionBone is constantly remodeled through the removal of old bone (resorption) and the replacement of new bone (formation) by hematopoietic-derived osteoclasts and mesenchymal-derived osteoblasts, respectively, to meet structural and metabolic demands (1, 2). It has long been believed that a preceding resorption phase is a prerequisite for the initiation of subsequent bone formation (3), which is also supported by recent clinical observations that treatment of osteoporotic patients with the potent antiresorptive drug alendronate blunts the anabolic action of parathyroid hormone (PTH) (4). Although the coupling of bone formation to resorption has been long recognized, the mechanism and the factors mediating this fundamental process in skeletal homeostasis are not fully understood (5).Recently, it was suggested that active TGF-β1 released from bone matrix during bone resorption is coupled to bone formation by inducing migration of marrow stromal cells to resorption sites (6). Bidirectional signaling between EPHRINB2 on osteoclasts and the receptor EPHB4 on osteoblasts has also been proposed to link bone resorption and formation through direct cell-cell contact (7). In addition, mature osteoclasts produce and secrete factors, such as WNT10B, BMP6, and the lipid mediator sphingosine-1-phosphate (S1P), that have been shown to stimulate osteoblast recruitment and survival (8-10). However, the in vivo function of these factors in the coupling process remains to be elucidated.We reasoned that a factor mediating the coupling reaction linking bone resorption to formation would have to meet the following criteria: (a) it should be produced and secreted/presented by osteoclasts; (b) it should exert a...

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Section: Coupling Function In Vivomentioning

confidence: 69%

Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation

Takeshita¹,

Fumoto²,

Matsuoka³

et al. 2013

J. Clin. Invest.

199

179

View full text Add to dashboard Cite

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“…[7][8][9][10]15,[34][35][36][37] As osteoblast precursors/ osteoblasts express membrane-bounded FASL and osteoclasts express FAS, 23,29 osteoblast-osteoclast contact is very likely to happen during the bone remodeling process. Thus, it is reasonable to assume that osteoblast lineage cells are capable of inducing osteoclast apoptosis to serve as an alternative mechanism to govern osteoclast activity.…”

Section: Discussionmentioning

confidence: 99%

Osteoblast-induced osteoclast apoptosis by fas ligand/FAS pathway is required for maintenance of bone mass

et al. 2015

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The interplay between osteoblasts and osteoclasts has a crucial role in maintaining bone homeostasis. In this study, we reveal that osteoblasts are capable of inducing osteoclast apoptosis by FAS ligand (FASL)/FAS signaling. Conditional knockout of FASL in osteoblasts results in elevated osteoclast numbers and activity, along with reduced bone mass, suggesting that osteoblastproduced FASL is required to maintain physiological bone mass. More interestingly, we show that osteoblasts from ovariectomized (OVX) osteoporotic mice exhibit decreased FASL expression that results from the IFN-γ-and TNF-α-activated NF-κB pathway, leading to reduced osteoclast apoptosis and increased bone resorption. Systemic administration of either IFN-γ or TNF-α ameliorates the osteoporotic phenotype in OVX mice and rescues FASL expression in osteoblasts. In addition, ovariectomy induces more significant bone loss in FASL conditional knockout mice than in control group with increased osteoclast activity in which the levels of RANKL and OPG remain unchanged. Taken together, this study suggests that osteoblast-induced osteoclast apoptosis via FASL/FAS signaling is a previously unrecognized mechanism that has an important role in the maintenance of bone mass in both physiological conditions and OVX osteoporosis.

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“…An adequate supply of osteoblasts from their stem cells, bone marrow MSCs, is critical for bone formation as osteoblasts are non-replicative (7). Particularly, bone remodeling is temporally and spatially controlled and occurs continuously throughout the lifespan to maintain bone mass and architecture (5,7,20,27,(29)(30). During bone resorption by osteoclasts, multiple growth factors and cytokines are acvitated and released from the bone matrix to recruit MSCs and induce differentiation into mature osteoblasts in coupling bone formation with resorption (5,20,29,(31)(32).…”

Section: Discussionmentioning

confidence: 99%

IGF-1 Signaling is Essential for Differentiation of Mesenchymal Stem Cells for Peak Bone Mass

et al. 2013

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Survival of children with chronic medical illnesses is leading to an increase in secondary osteoporosis due to impaired peak bone mass (PBM). Insulin-like growth factor type 1 (IGF-1) levels correlate with the pattern of bone mass accrual and many chronic illnesses are associated with low IGF-1 levels. Reduced serum levels of IGF-1 minimally affect the integrity of the skeleton, whereas recent studies suggest that skeletal IGF-I regulates PBM. To determine the role of IGF-1 in postnatal bone mass accrual regardless of source, we established an inducible type 1 Igf receptor Cre/lox knockout mouse model, in which the type 1 Igf receptor was deleted inducibely in the mesenchymal stem cells (MSCs) from 3-7 weeks of age. The size of the mouse was not affected as knockout and wild type mice had similar body weights and nasoanal and femoral lengths. However, bone volume and trabecular bone thickness were decreased in the secondary spongiosa of female knockout mice relative to wild type controls, indicating that IGF-1 is critical for bone mass. IGF-1 signaling in MSCs in vitro has been implicated to be involved in both migration to the bone surface and differentiation into bone forming osteoblasts. To clarify the exact role of IGF-1 in bone, we found by immunohistochemical analysis that a similar number of Osterix-positive osteoprogenitors were on the bone perimeter, indicating migration of MSCs was not affected. Most importantly, 56% fewer osteocalcin-positive mature osteoblasts were present on the bone perimeter in the secondary spongiosa in knockout mice versus wild type littermates. These in vivo data demonstrate that the primary role of skeletal IGF-1 is for the terminal differentiation of osteoprogenitors, but refute the role of IGF-1 in MSC migration in vivo. Additionally, these findings confirm that impaired IGF-1 signaling in bone MSCs is sufficient to impair bone mass acquisition. Keywords: osteoblasts; knockout mice; cell migration; IGF receptor; nestin Bone Research (2013) 2: 186-194. doi: 10.4248 /BR201302007 IntroductionBone mass normally peaks in mid to late adolescence, plateaus for several years and then declines over time (1-5). Acquisition of a higher peak bone mass (PBM) in adolescence is associated with reduced subsequent fracture risk, whereas impaired acquisition of PBM or loss of bone in childhood is associated with greater fracture risk. Chronic illness in childhood impairs PBM acquisition. Survival of many chronic illnesses in childhood are leading to a growing incidence of secondary osteoporosis (6). The prevention of secondary osteoporosis in children with chronic illnesses depends on protecting the bones of this at-risk population. However, before treatment can be developed, the regulation of cellular signaling mechanisms involved in the acquisition of bone mass needs to be further elucidated.Janet L. Crane et al. www.boneresearch.org | Bone Research 187The only cells that form new bone are osteoblasts, which are non-replicative mononuclear cells derived from mesenchymal stem cells (MSC) (7-...

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Inhibition of Sca-1-Positive Skeletal Stem Cell Recruitment by Alendronate Blunts the Anabolic Effects of Parathyroid Hormone on Bone Remodeling

Cited by 119 publications

References 42 publications

Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation

Osteoclast-secreted CTHRC1 in the coupling of bone resorption to formation

Osteoblast-induced osteoclast apoptosis by fas ligand/FAS pathway is required for maintenance of bone mass

IGF-1 Signaling is Essential for Differentiation of Mesenchymal Stem Cells for Peak Bone Mass

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