Therapeutic Effects of Kefir Peptides on Hemophilia-Induced Osteoporosis in Mice With Deficient Coagulation Factor VIII

Abstract

Osteoporosis is a clinically prevalent comorbidity in patients with hemophilia. A preventive effect of kefir peptides (KPs) on postmenopausal osteoporosis has been proved. The aim of this study was to evaluate the therapeutic effect of KPs for the treatment of osteoporosis in coagulation factor VIII (FVIII) gene knockout mice (F8KO), a model of hemophilia A. In this study, male F8KO mice at 20 weeks of age were orally administered different doses of KPs for 8 weeks. The therapeutic effects of KPs were shown in the femoral trabeculae and the 4th lumbar vertebrae, which increased the trabecular bone mineral density (BMD), bone volume (Tb.BV/TV), and trabecular number (Tb.N) and decreased the trabecular separation (Tb.Sp), and they were also observed in the femoral cortical bones, in which the mechanical properties were enhanced in a dose-dependent manner. Characterization of receptor activator of nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), and interleukin 6 (IL-6) demonstrated that the serum RANKL/OPG ratio and IL-6 levels were significantly decreased in the F8KO mice after the KP treatment. Tartrate-resistant acid phosphatase (TRAP) staining of mature osteoclasts indicated that the therapeutic effect of KPs in F8KO mice was associated with the functions of KPs to inhibit RANKL-induced osteoclastogenesis by reducing serum RANKL/OPG ratio and IL-6 secretion. The present study is the first to address the potentials of KPs for the treatment of hemophilia-induced osteoporosis in mice and it also provides useful information for the application of KPs as a complementary therapy for the treatment of osteoporosis in hemophilic patients.

Kefir peptides attenuate atherosclerotic vascular calcification and osteoporosis in atherogenic diet-fed ApoE−/− knockout mice

“…Concomitantly, KP treatment improved BMD and microarchitecture in trabecular ( Figure 4 ) and cortical bones ( Figure 5 ) with an increase in the circulating bone formation marker P1NP and a reduction in the resorption marker CTX1 ( Figure 6 ), which showed that bone remodeling favored bone formation in KP-treated ApoE −/− mice. In fact, KPs have repeatedly demonstrated bone-protective benefits in our earlier animal models of osteoporosis caused by estrogen depletion ( Chen et al, 2015 ; Tu et al, 2020 ), hemophilia ( Yen et al, 2022 ), and vitamin C insufficiency ( Chang et al, 2022 ), and rats with glucocorticoid-induced osteoporosis ( de Vasconcelos et al, 2022 ). We recently demonstrated that KPs promoted osteoblastic differentiation and bone mineralization while inhibiting RANKL-induced osteoclastic differentiation and bone resorption in vitro ( Chang et al, 2022 ), and treatments with KPs eventually lowered the circulating RANKL/OPG ratio in vivo ( Chang et al, 2022 ; Yen et al, 2022 ).…”

“…In fact, KPs have repeatedly demonstrated bone-protective benefits in our earlier animal models of osteoporosis caused by estrogen depletion ( Chen et al, 2015 ; Tu et al, 2020 ), hemophilia ( Yen et al, 2022 ), and vitamin C insufficiency ( Chang et al, 2022 ), and rats with glucocorticoid-induced osteoporosis ( de Vasconcelos et al, 2022 ). We recently demonstrated that KPs promoted osteoblastic differentiation and bone mineralization while inhibiting RANKL-induced osteoclastic differentiation and bone resorption in vitro ( Chang et al, 2022 ), and treatments with KPs eventually lowered the circulating RANKL/OPG ratio in vivo ( Chang et al, 2022 ; Yen et al, 2022 ). Although serum RANKL and OPG levels were not measured at the end of this study, it was speculated that KP treatment could lower the serum RANKL/OPG ratio in the current ApoE −/− model.…”

“…The microbial composition of kefir grains includes a variety of probiotics, such as lactobacteria, acetic acid bacteria, and yeasts, which degrade milk proteins into abundant bioactive peptides called kefir peptides (KPs) that exert multiple functions, such as antioxidation, anti-inflammation, and immunomodulation ( Rosa et al, 2017 ). We previously demonstrated the bone-protective effects of KPs in a variety of osteoporotic animal models and osteoporotic patients ( Chen et al, 2015 ; Tu et al, 2015 ; Tu et al, 2020 ; Chang et al, 2022 ; Yen et al, 2022 ) and reported the anti-atherosclerotic activity of KPs in ApoE −/− mice fed high-fat diets ( Tung et al, 2020 ). The present study further elucidated the preventive effects of KPs on VC and osteoporosis in ApoE −/− mice.…”

The Roles of RANK/RANKL/OPG in Cardiac, Skeletal, and Smooth Muscles in Health and Disease

“…Another study showed that thrombin receptor deficiency leads to a decrease in RANKL/OPG ratio which was associated with a high bone density phenotype ( Tudpor et al, 2015 ). Conversely, a significant increase in the RANKL/OPG ratio and signs of osteoporosis were noticed in a mouse model of hemophilia ( Yen et al, 2022 ). Moreover, OPG may play a role in regulating thrombus formation by binding to Von Willebrand factor (VWF), an essential factor for platelet adhesion ( Wohner et al, 2022 ).…”

Combate a Depressão Com O Uso Do Chá Da Mimosa Tenuiflora(willd.) Poir., Popularmente Conhecida Como “Jurema-Preta”

“…A osteoporose se caracteriza por uma desordem osteometabólica sistêmica que desencadeia redução da densidade mineral óssea (DMO) e deterioração da microarquitetura óssea, no entanto, sua etiologia varia de acordo com o mecanismo da perda óssea (YEN et al, 2022). Dessa forma, ela pode ser classificada em primária ou secundária.…”