Gut Metabolite Urolithin A Inhibits Osteoclastogenesis and Senile Osteoporosis by Enhancing the Autophagy Capacity of Bone Marrow Macrophages

Abstract

Senile osteoporosis (SOP) is a systemic bone disease that is significantly associated with age and eventually leads to deteriorated bone strength and increased fracture risk. Urolithin A (Uro-A) is a gut microbiome-derived compound that is mainly produced from pomegranates and some nuts. Uro-A has attracted great attention in recent years in view of its protective effects on aging-related diseases, including muscle dysfunction, kidney disease and knee injury. However, its protective influence and possible mechanisms in senile osteoporosis remain unclear. Our study describes the beneficial effect of Uro-A on bone marrow macrophages (BMMs). The in vitro results demonstrated that Uro-A inhibited receptor activator for nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in BMMs in a concentration-dependent manner. Uro-A significantly reduced the expression of osteoclast-related genes and bone resorption. Mechanistically, we found that the autophagy ability of BMMs was significantly enhanced in the early stage of Uro-A treatment, accompanied by the activation of LC3 and Beclin 1. At the same time, this enhanced autophagy activity was maintained until the later stage after stimulation with RANKL. Furthermore, we found that the MARK signaling pathway was blocked by Uro-A treatment. In a mouse model of aging, Uro-A effectively inhibited bone loss in the proximal femur, spine and tibia of aging mice. These results indicated that Uro-A is a robust and effective treatment for preventing senile osteoporosis bone loss.

Bone health: biology and nutrition

“…The trial duration was too short to assess BMD changes. However, several preclinical studies have demonstrated an inhibition of osteoclastogenesis and a decrease in experimental bone loss, raising some hope on the effect of urolithin A on bone health [ 49 , 50 ].…”

Urolithin A as a Potential Agent for Prevention of Age-Related Disease: A Scoping Review

“…The final three musculoskeletal-related studies focus on age-related bone and joint pathology [ 21 , 22 ]. UA supplementation has also shown promise as an anti-aging remedy in the development of osteoporosis [ 21 ].…”

“…The final three musculoskeletal-related studies focus on age-related bone and joint pathology [ 21 , 22 ]. UA supplementation has also shown promise as an anti-aging remedy in the development of osteoporosis [ 21 ]. In a 2022 study completed by Tao et al, a significant reduction in bone resorption and osteoclast-related gene expression was seen in human cell samples treated with 5 and 10 μM doses of UA [ 21 ].…”

“…UA supplementation has also shown promise as an anti-aging remedy in the development of osteoporosis [ 21 ]. In a 2022 study completed by Tao et al, a significant reduction in bone resorption and osteoclast-related gene expression was seen in human cell samples treated with 5 and 10 μM doses of UA [ 21 ]. Treatment with UA also enhanced autophagic activity in bone marrow macrophages, and this increase was maintained after stimulation of increased osteoclastogenesis via the receptor activator of the nuclear factor 𝜅B ligand (RANKL) pathway [ 21 ].…”

“…In a 2022 study completed by Tao et al, a significant reduction in bone resorption and osteoclast-related gene expression was seen in human cell samples treated with 5 and 10 μM doses of UA [ 21 ]. Treatment with UA also enhanced autophagic activity in bone marrow macrophages, and this increase was maintained after stimulation of increased osteoclastogenesis via the receptor activator of the nuclear factor 𝜅B ligand (RANKL) pathway [ 21 ]. Current evidence also suggests that osteoarthritic disease progression may be altered by UA supplementation [ 22 ].…”