Abstract
Impaired bone formation is one of the major causes of low bone mass and skeletal fragility that occurs in osteoporosis. However, the mechanisms underlying the defects in bone formation are not well understood. Here, we report that big conductance calcium-activated potassium channels (BKs) are required for bone formation and osteoblast function both in vivo and in vitro. By 15 weeks of age, BK knockout (BKO) mice exhibited a decline in bone mineral density and trabecular bone volume of the tibiae and lumbar vertebrae, which were associated with impaired bone formation and osteoblast activity. Mechanistically, BK ablation in bone and bone marrow mesenchymal stem cells (BMSCs) of BKO mice inhibited integrin signaling. Furthermore, the binding of α subunit of BK with integrin β1 protein in osteoblasts was confirmed, and FAK-ERK1/2 signaling was proved to be involved by genetic modification of KCNMA1 (which encodes the α subunit of BK) in ROS17/2.8 osteoblast cells. These findings indicated that BK regulates bone formation by promoting osteoblast differentiation via integrin pathway, which provided novel insight into ion transporter crosstalk with the extracellular matrix in osteoblast regulation and revealed a new potential strategy for intervention in correcting bone formation defects.
Highlights
Defects in bone formation in response to the accelerated bone resorption cause an imbalance in bone remodeling resulting in low bone mass and skeletal fragility in osteoporosis[1,2]
BV/TV) in the tibia of big conductance Kca (BK) knockout (BKO) mice was markedly decreased by 56.80% (P < 0.05) compared with that of their wild-type (WT) littermates; the trabecular thickness (Tb.Th) was decreased by 17.83% (P < 0.05), and the trabecular number (Tb.N) was decreased by 47.50% (P < 0.05), whereas trabecular separation (Tb.Sp) was increased by 130.68% (P = 0.06) (Fig. 1e)
The osteoblast activities, which were evaluated by osteoblast perimeter (Ob.Pm/Tb.Pm), mineral apposition rate (MAR) and bone formation rate (BFR/B.S) were decreased in BKO mice, with no or modest changes in osteoclast activity
Summary
Defects in bone formation in response to the accelerated bone resorption cause an imbalance in bone remodeling resulting in low bone mass and skeletal fragility in osteoporosis[1,2] These defects are characterized by a decrease in cell number and function of osteoblasts that are thought to be related to a decline in growth factors (e.g., insulin-like growth factor-1, IGF-1), a deficiency of estrogen and androgen, an accumulation of tumor necrosis factor alpha (TNFα) or ageing;[3,4,5] the detailed mechanisms underlying changes in osteoblast functional responses are not understood. Potassium channels are a diverse family of membrane proteins that include calcium (Ca2+)-activated potassium channels (termed Kca), voltage-gated potassium (K+) channels (termed Kv) and others (K2p and Kir channels)[7,8].
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