Fig. 1. Anabolic insulin receptor (InsR) signaling in osteoblasts versus proinflammatory cytokine-induced osteoclastic activity. In patients with metabolic dysfunction-associated steatotic liver disease (MASLD), the major forces determining bone formation and bone resorption are anabolic InsR signaling in osteoblasts and proinflammatory cytokine-induced osteoclastic activity, respectively. In early MASLD (steatosis stage), mild insulin resistance and low levels of proinflammatory cytokines may cause the anabolic InsR signaling to predominate in osteoblasts, resulting in net bone gain. When insulin resistance (leading to moderate loss of anabolic InsR signaling) and the level of inflammatory cytokines (leading to increased osteoclastic activity) are moderate, the two processes may balance each other, resulting in no net bone change. Last, when insulin resistance worsens (mild/no anabolic InsR signaling) and higher amounts of proinflammatory cytokines are present, osteoclastic activity may predominate, resulting in net bone loss. Advanced fibrosis and cirrhosis stages are associated with predominant osteoclastic activity. GH, growth hormone; IGF-1, insulin-like growth factor-1; MASH, metabolic dysfunction-associated steatohepatitis.
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