Time course of disassociation of bone formation signals with bone mass and bone strength in sclerostin antibody treated ovariectomized rats

Li, Yanfei; Hamang, Matthew; Lucchesi, Jonathan; Bivi, Nicoletta; Zeng, Q.Q; Adrian, Mary D.; Raines, Sarah E; Li, Jiliang; Kuhstoss, Stuart; Obungu, Victor H.; Bryant, Henry U.; Krishnan, Venkatesh

doi:10.1016/j.bone.2016.12.003

Cited by 19 publications

(14 citation statements)

References 49 publications

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“…Nioi and colleagues observed that Bglap and Col1a1 were significantly upregulated in osteoblast lineage cells following one dose of SclAb in an OVX rat model, indicating a bone‐forming response can be both acute and robust . Our findings are supportive of Nioi and colleagues and others where we observed that SclAb treatment elicited an early bone‐forming response through upregulation of COL1A1 and BGLAP in nearly all treated OI samples . This upregulation following short‐term treatment reflects initial stages of bone anabolism consistent with an eventual increase in osteoblast differentiation.…”

Section: Discussionsupporting

confidence: 88%

“…(40) Our findings are supportive of Nioi and colleagues and others where we observed that SclAb treatment elicited an early bone-forming response through upregulation of COL1A1 and BGLAP in nearly all treated OI samples. (40,44,58) This upregulation following short-term treatment reflects initial stages of bone anabolism consistent with an eventual increase in osteoblast differentiation. Taken together with WISP1 upregulation, our results suggest an increase in bone-forming activity and evidence of a concurrent decrease in resorptive activity.…”

Section: Discussionmentioning

confidence: 88%

“…Specifically, downstream Wnt targets ( WISP1 , TWIST1 ), inhibitory regulators of bone formation ( SOST , DKK1 ), markers of osteoblastogenesis ( SP7 , RUNX2 ), osteoblast markers ( BGLAP , COL1A1 ), and markers of osteoclast differentiation and activity ( OPG , RANKL ) were evaluated. The panel represents a subset of markers in the bone remodeling cycle—many of which have been identified as key targets for SclAb therapy in prior animal studies . Because of the rarity of the OI bone tissue and the size of the available harvested bone (which affected the amount of total nucleic acid we were able to extract), we chose to analyze only one housekeeping gene ( HPRT1 ), which has been documented in the literature as a stable gene across experimental conditions in human bone studies …”

Section: Methodsmentioning

confidence: 99%

“…The panel represents a subset of markers in the bone remodeling cycle-many of which have been identified as key targets for SclAb therapy in prior animal studies. (38)(39)(40)44) Because of the rarity of the OI bone tissue and the size of the available harvested bone (which affected the amount of total nucleic acid we were able to extract), we chose to analyze only one housekeeping gene (HPRT1), which has been documented in the literature as a stable gene across experimental conditions in human bone studies. (45,46) Pooled, purified RNA samples underwent reverse transcription using qScript cDNA SuperMix (Quanta Biosciences, Gaithersburg, MD, USA) using 1.5 μg of retro-transcribed RNA per reaction followed by thermocycling (C1000 Thermal Cycler; Bio-Rad Laboratories, Hercules, CA, USA) according to the manufacturer's recommendations.…”

Section: Taqman Qpcr Analysismentioning

confidence: 99%

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Gene Expression Profile and Acute Gene Expression Response to Sclerostin Inhibition in Osteogenesis Imperfecta Bone

et al. 2020

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Sclerostin antibody (SclAb) therapy has been suggested as a novel therapeutic approach toward addressing the fragility phenotypic of osteogenesis imperfecta (OI). Observations of cellular and transcriptional responses to SclAb in OI have been limited to mouse models of the disorder, leaving a paucity of data on the human OI osteoblastic cellular response to the treatment. Here, we explore factors associated with response to SclAb therapy in vitro and in a novel xenograft model using OI bone tissue derived from pediatric patients. Bone isolates (approximately 2 mm3) from OI patients (OI type III, type III/IV, and type IV, n = 7; non‐OI control, n = 5) were collected to media, randomly assigned to an untreated (UN), low‐dose SclAb (TRL, 2.5 μg/mL), or high‐dose SclAb (TRH, 25 μg/mL) group, and maintained in vitro at 37°C. Treatment occurred on days 2 and 4 and was removed on day 5 for TaqMan qPCR analysis of genes related to the Wnt pathway. A subset of bone was implanted s.c. into an athymic mouse, representing our xenograft model, and treated (25 mg/kg s.c. 2×/week for 2/4 weeks). Implanted OI bone was evaluated using μCT and histomorphometry. Expression of Wnt/Wnt‐related targets varied among untreated OI bone isolates. When treated with SclAb, OI bone showed an upregulation in osteoblast and osteoblast progenitor markers, which was heterogeneous across tissue. Interestingly, the greatest magnitude of response generally corresponded to samples with low untreated expression of progenitor markers. Conversely, samples with high untreated expression of these markers showed a lower response to treatment. in vivo implanted OI bone showed a bone‐forming response to SclAb via μCT, which was corroborated by histomorphometry. SclAb induced downstream Wnt targets WISP1 and TWIST1, and elicited a compensatory response in Wnt inhibitors SOST and DKK1 in OI bone with the greatest magnitude from OI cortical bone. Understanding patients' genetic, cellular, and morphological bone phenotypes may play an important role in predicting treatment response. This information may aid in clinical decision‐making for pharmacological interventions designed to address fragility in OI. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Section: Taqman Qpcr Analysismentioning

confidence: 99%

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Gene Expression Profile and Acute Gene Expression Response to Sclerostin Inhibition in Osteogenesis Imperfecta Bone

et al. 2020

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“…Additionally, the sclerostin antibody stimulated bone formation and inhibited bone resorption in a rat model . Sclerostin antibodies increased cortical bone volume and improved bone strength in ovariectomized rat model . Therefore, our study aimed to confirm whether SOST/sclerostin was involved in periprosthetic osteolysis.…”

Section: Discussionmentioning

confidence: 93%

Reduction of SOST gene promotes bone formation through the Wnt/β‐catenin signalling pathway and compensates particle‐induced osteolysis

Zhang

Jia

Fang

et al. 2020

J Cellular Molecular Medi

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The increase in bone resorption and/or the inhibition of bone regeneration caused by wear particles are the main causes of periprosthetic osteolysis. The SOST gene and Sclerostin, a protein synthesized by the SOST gene, are the characteristic marker of osteocytes and regulate bone formation and resorption. We aimed to verify whether the SOST gene was involved in osteolysis induced by titanium (Ti) particles and to investigate the effects of SOST reduction on osteolysis. The results showed osteolysis on the skull surface with an increase of sclerostin levels after treated with Ti particles. Similarly, sclerostin expression in MLO-Y4 osteocytes increased when treated with Ti particles in vitro. After reduction of SOST, local bone mineral density and bone volume increased, while number of lytic pores on the skull surface decreased and the erodibility of the skull surface was compensated. Histological analyses revealed that SOST reduction increased significantly alkaline phosphatase-(ALP) and osterix-positive expression on the skull surface which promoted bone formation. ALP activity and mineralization of MC3T3-E1 cells also increased in vitro when SOST was silenced, even if treated with Ti particles. In addition, Ti particles decreased β-catenin expression with an increase in sclerostin levels, in vivo and in vitro. Inversely, reduction of SOST expression increased β-catenin expression. In summary, our results suggested that reduction of SOST gene can activate the Wnt/β-catenin signalling pathway, promoting bone formation and compensated for bone loss induced by Ti particles. Thus, this study provided new perspectives in understanding the mechanisms of periprosthetic osteolysis. K E Y W O R D S osteoblast, osteocyte, osteolysis, SOST/sclerostin, wear debris

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Mechanically Driven Counter-Regulation of Cortical Bone Formation in Response to Sclerostin-Neutralizing Antibodies

Gerbaix

Ammann

Ferrari

2020

Journal of Bone and Mineral Research

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Sclerostin (Scl) antibodies (Scl‐Ab) potently stimulate bone formation, but these effects are transient. Whether the rapid inhibition of Scl‐Ab anabolic effects is due to a loss of bone cells’ capacity to form new bone or to a mechanostatic downregulation of Wnt signaling once bone strength exceeds stress remains unclear. We hypothesized that bone formation under Scl‐Ab could be reactivated by increasing the dose of Scl‐Ab and/or by adding mechanical stimuli, and investigated the molecular mechanisms involved in this response, in particular the role of periostin (Postn), a co‐activator of the Wnt pathway in bone. For this purpose, C57Bl/6, Postn−/− and Postn+/+ mice were treated with vehicle or Scl‐Ab (50 to 100 mg/kg/wk) for various durations and subsequently subjected to tibia axial compressive loading. In wild‐type (WT) mice, Scl‐Ab anabolic effects peaked between 2 and 4 weeks and declined thereafter, with no further increase in bone volume and strength between 7 and 10 weeks. Doubling the dose of Scl‐Ab did not rescue the decline in bone formation. In contrast, mechanical stimulation was able to restore cortical bone formation concomitantly to Scl‐Ab treatment at both doses. Several Wnt inhibitors, including Dkk1, Sost, and Twist1, were upregulated, whereas Postn was markedly downregulated by 2 to 4 weeks of Scl‐Ab. Mechanical loading specifically upregulated Postn gene expression. In turn, Scl‐Ab effects on cortical bone were more rapidly downregulated in Postn−/− mice. These results indicate that bone formation is not exhausted by Scl‐Ab but inhibited by a mechanically driven downregulation of Wnt signaling. Hence, increasing mechanical loads restores bone formation on cortical surfaces, in parallel with Postn upregulation. © 2020 American Society for Bone and Mineral Research (ASBMR).

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Time course of disassociation of bone formation signals with bone mass and bone strength in sclerostin antibody treated ovariectomized rats

Cited by 19 publications

References 49 publications

Gene Expression Profile and Acute Gene Expression Response to Sclerostin Inhibition in Osteogenesis Imperfecta Bone

Gene Expression Profile and Acute Gene Expression Response to Sclerostin Inhibition in Osteogenesis Imperfecta Bone

Reduction of SOST gene promotes bone formation through the Wnt/β‐catenin signalling pathway and compensates particle‐induced osteolysis

Mechanically Driven Counter-Regulation of Cortical Bone Formation in Response to Sclerostin-Neutralizing Antibodies

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