Abstract
Osteoclasts are of hematopoietic lineage and have the ability to degrade mineralized bone tissues. Abnormalities in osteoclastic activity under certain pathological conditions are common in bone diseases such as osteoporosis, osteosclerosis, and arthritis. Although many kinds of drugs are currently used to treat osteoporosis, they have obvious adverse reactions and limitations. CYT387 is a new small-molecule Janus kinase (JAK) inhibitor involved in hematopoiesis, immune modulation, fertility, lactation, and embryonic development. However, it has remained unclear whether CYT387 functionally impacts osteoclast formation. Our study demonstrated through osteoclast formation assay in vitro, that the use of CYT387 is a potential drug candidate for treating osteoclast-associated bone disease. The effects of CYT387 on osteoclast formation, bone resorption, NFATc1 activation, and especially intracellular ROS levels were investigated in vitro. Further, we examined the preclinical prospects of CYT387 using an oophorectomy (OVX) mouse model of osteoporosis with its anti-osteoclast activity in vivo. On the whole, this study shows that CYT387 holds promise for treating osteoclast-related bone illnesses including osteoporosis.
Highlights
The bone is an extremely dynamic organ that is constantly renewed and reshaped throughout its lifespan, even in adults (Shih and Varghese, 2019)
To clarify whether the cytotoxicity of CYT387 is involved in the inhibition of osteoclast formation, we examined cell viability utilizing Cell Counting kit-8 (CCK-8)
We observed a significant reduction in the number of tartrateresistant acid phosphatase (TRAcP)-positive cells at 1–3 and 3–5 days compared with Bone marrow-derived macrophages (BMMs) stimulated only by receptor activator of nuclear factor kappa-B ligand (RANKL) (Figures 1D,F)
Summary
The bone is an extremely dynamic organ that is constantly renewed and reshaped throughout its lifespan, even in adults (Shih and Varghese, 2019). It maintains structural integrity including healthy bone mass and strength, through constant degradation and regeneration (Harmer et al, 2019). When the equilibrium in the osteoblast-mediated bone synthesis and osteoclast-mediated bone resorption is disrupted (Shih et al, 2019), such as in female menopause, decreases in bone mass will occur, accompanied by an increase in structural space within the bone marrow, eventually leading to osteoporosis (He et al, 2012). With an increase in the senior-citizen segment in the population, the number of osteoporosis patients has been rapidly increasing, placing a heavy economic burden on society
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