Blocking CCN2 preferentially inhibits osteoclastogenesis induced by repetitive high force bone loading

Barbe, Mary F.; Amin, Mamta; Gingery, Anne; Lambi, Alex G.; Popoff, Steven N.

doi:10.1080/03008207.2020.1788546

Cited by 6 publications

(34 citation statements)

References 42 publications

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“…Rat care details are as previously described. [7] Experimental design is shown in Figure 1. Controls included food-restricted control rats (FRC) that were food restricted to 5% less than age-matched normal control rats (the latter not included in this study), similar to task rats, yet no exposure to operant shaping or task performance.…”

Section: Overview Of Animalsmentioning

confidence: 99%

Blocking CCN2 Reduces Established Bone Loss Induced by Prolonged Intense Loading by Increasing Osteoblast Activity in Rats

et al. 2023

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We have an operant model of reaching and grasping in which detrimental bone remodeling is observed rather than beneficial adaptation when rats perform a high‐repetition, high‐force (HRHF) task long term. Here, adult female Sprague–Dawley rats performed an intense HRHF task for 18 weeks, which we have shown induces radial trabecular bone osteopenia. One cohort was euthanized at this point (to assay the bone changes post task; HRHF‐Untreated). Two other cohorts were placed on 6 weeks of rest while being simultaneously treated with either an anti‐CCN2 (FG‐3019, 40 mg/kg body weight, ip; twice per week; HRHF‐Rest/anti‐CCN2), or a control IgG (HRHF‐Rest/IgG), with the purpose of determining which might improve the trabecular bone decline. Results were compared with food‐restricted control rats (FRC). MicroCT analysis of distal metaphysis of radii showed decreased trabecular bone volume fraction (BV/TV) and thickness in HRHF‐Untreated rats compared with FRCs; responses improved with HRHF‐Rest/anti‐CCN2. Rest/IgG also improved trabecular thickness but not BV/TV. Histomorphometry showed that rest with either treatment improved osteoid volume and task‐induced increases in osteoclasts. Only the HRHF‐Rest/anti‐CCN2 treatment improved osteoblast numbers, osteoid width, mineralization, and bone formation rate compared with HRHF‐Untreated rats (as well as the latter three attributes compared with HRHF‐Rest/IgG rats). Serum ELISA results were in support, showing increased osteocalcin and decreased CTX‐1 in HRHF‐Rest/anti‐CCN2 rats compared with both HRHF‐Untreated and HRHF‐Rest/IgG rats. These results are highly encouraging for use of anti‐CCN2 for therapeutic treatment of bone loss, such as that induced by chronic overuse. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Section: Overview Of Animalsmentioning

confidence: 99%

Blocking CCN2 Reduces Established Bone Loss Induced by Prolonged Intense Loading by Increasing Osteoblast Activity in Rats

et al. 2023

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“…While it may seem a surprise to see osteoblast numbers at control levels in the trabeculae of 12-week TASK rats, they are increased in distal metaphyseal trabeculae immediately after the initial shaping period (TASK week 0) and in 3-week TASK rats compared to controls [ 46 ]. Apparently, short-term loading of this intensive task induces osteogenesis but not prolonged long-term loading.…”

Section: Discussionmentioning

confidence: 99%

“…These sections were dried onto charged slides using slide warming plates overnight before being stored at room temperature until use, at which point they were deparaffinized in xylene and decreasing concentrations of ethanols before staining. Sections with radial bone underwent Masson’s Trichrome or Safranin O/Fast Green staining or immunohistochemical staining with either an anti-TRAP or CD68+ antibody using previously described methods [ 10 , 46 ]. Specificity of the TRAP antibody has been previously described, as has the detection of TRAP+ cells by CD68 immunostaining [ 10 , 46 ].…”

Section: Methodsmentioning

confidence: 99%

“…Sections with radial bone underwent Masson’s Trichrome or Safranin O/Fast Green staining or immunohistochemical staining with either an anti-TRAP or CD68+ antibody using previously described methods [ 10 , 46 ]. Specificity of the TRAP antibody has been previously described, as has the detection of TRAP+ cells by CD68 immunostaining [ 10 , 46 ]. Only multinucleated TRAP+ or CD68+ cells were counted with the bone to quantify osteoclasts.…”

Section: Methodsmentioning

confidence: 99%

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Manual Therapy Facilitates Homeostatic Adaptation to Bone Microstructural Declines Induced by a Rat Model of Repetitive Forceful Task

Barbe

Amin

Harris

et al. 2022

IJMS

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The effectiveness of manual therapy in reducing the catabolic effects of performing repetitive intensive force tasks on bones has not been reported. We examined if manual therapy could reduce radial bone microstructural declines in adult female Sprague–Dawley rats performing a 12-week high-repetition and high-force task, with or without simultaneous manual therapy to forelimbs. Additional rats were provided 6 weeks of rest after task cessation, with or without manual therapy. The control rats were untreated or received manual therapy for 12 weeks. The untreated TASK rats showed increased catabolic indices in the radius (decreased trabecular bone volume and numbers, increased osteoclasts in these trabeculae, and mid-diaphyseal cortical bone thinning) and increased serum CTX-1, TNF-α, and muscle macrophages. In contrast, the TASK rats receiving manual therapy showed increased radial bone anabolism (increased trabecular bone volume and osteoblast numbers, decreased osteoclast numbers, and increased mid-diaphyseal total area and periosteal perimeter) and increased serum TNF-α and muscle macrophages. Rest, with or without manual therapy, improved the trabecular thickness and mid-diaphyseal cortical bone attributes but not the mineral density. Thus, preventive manual therapy reduced the net radial bone catabolism by increasing osteogenesis, while rest, with or without manual therapy, was less effective.

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“…The targeting of CCN2/CTGF using a therapeutic monoclonal antibody approach has recently attracted significant interest as a novel anti-fibrotic treatment for skeletal muscle, and Barbe and colleagues 16 contribute further insights by evaluating how bone responds to such treatments. In their chronic, upper extremity overuse model known to produce skeletal muscle and tendon fibrosis, blocking CCN2/CTGF enhanced the anabolic loading effect on bone and ameliorated trabecular bone loss.…”

Section: Novel Applications Of Treatments and Interventionsmentioning

confidence: 99%

Cross-talk with skeletal muscle and its nexus with regenerative rehabilitation

Greising

Wang

2020

Connective Tissue Research

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Blocking CCN2 preferentially inhibits osteoclastogenesis induced by repetitive high force bone loading

Cited by 6 publications

References 42 publications

Blocking CCN2 Reduces Established Bone Loss Induced by Prolonged Intense Loading by Increasing Osteoblast Activity in Rats

Blocking CCN2 Reduces Established Bone Loss Induced by Prolonged Intense Loading by Increasing Osteoblast Activity in Rats

Manual Therapy Facilitates Homeostatic Adaptation to Bone Microstructural Declines Induced by a Rat Model of Repetitive Forceful Task

Cross-talk with skeletal muscle and its nexus with regenerative rehabilitation

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