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Autosomal dominant osteopetrosis type II (ADO II), characterized by increased bone mass and density, is caused by mutations in the chloride channel 7 (CLCN7) gene. In this study, a novel missense variant in CLCN7 (c.1678A > G; p.Met560Val) was identified in three symptomatic subjects and one carrier of a Chinese family with ADO II. Notably, bone formation markers, including osteocalcin and total procollagen type N-terminal propeptide, have increased or presented at the upper limit of the normal range in the three patients. Serum factors secreted by osteoclast lineage cells and affecting the CD31hiEMCNhi vessel formation, such as tartrate-resistant acid phosphatase 5b, platelet-derived growth factor-BB, vascular endothelial growth factor, and SLIT3, had a higher expression in three ADO II subjects than in 15 healthy age-matched and sex-matched controls. Moreover, the conditioned medium was obtained from preosteoclast induced from the ADO II patients’ peripheral blood mononuclear cells. It was found to promote the CD31hiEMCNhi vessel formation of human microvascular endothelial cells and osteogenic differentiation of bone marrow-derived stem cells. Taken together, our finding revealed a novel CLCN7 variant associated with ADO II and suggested that the sclerotic bone was potentially associated with the increase of the CD31hiEMCNhi vessel formation and bone formation.

Gushukang (GSK) is a traditional herbal compound used in Chinese medicine for the treatment of osteoporosis. Numerous studies have been conducted to elucidate the effects of GSK, but the mechanisms underlying these effects remain unclear. In the present study, we cultured osteoblasts and osteoclasts with low and high doses of GSK, and also administered 3-month-old mice with 4 and 8 g/kg/day of GSK solution. Gushukang was found to promote osteoblast differentiation and inhibit osteoclast differentiation in vitro. In vivo, mice in the GSK treatment groups showed an increase in bone mass, as measured by micro-computed tomography (Micro-CT). Tartrate resistant acid phosphatase (TRAP) staining and osteocalcin (OCN) staining experiments revealed decreased bone resorption and increased bone formation in the GSK treatment groups. In addition, we found a novel effect of GSK—it could induce type-H vessel formation in mice. The underlying mechanisms of these actions were further explored at the molecular level to investigate whether these effects were due to an overexpression of the hypoxia inducible factor-1 (HIF-1α). Our findings indicate the utility of GSK as a therapeutic for the prevention of osteoporosis.