Enzyme replacement therapy prevents loss of bone and fat mass in murine homocystinuria

Abstract

Skeletal and connective tissue defects are the most striking symptoms in patients suffering from classical homocystinuria (HCU). Here, we determined body composition and bone mass in three mouse models of HCU and assessed whether a long-term administration of enzyme replacement therapy (ERT) corrected the phenotype. The mouse models of HCU were analyzed using dual-energy X-ray absorptiometry and the data were complemented by plasma biochemical profiles. Both the mouse model lacking CBS (KO) and the one expressing human CBS mutant transgene on a mouse CBS null background (I278T) showed marked bone loss and decreased weight mostly due to a lower fat content compared with negative controls. In contrast, the HO mouse expressing the human CBS WT transgene on a mouse CBS null background showed no such phenotype despite similar plasma biochemical profile to the KO and I278T mice. More importantly, administration of ERT rescued bone mass and changes in body composition in the KO mice treated since birth and reversed bone loss and improved fat content in the I278T mice injected after the development of clinical symptoms. Our study suggests that ERT for HCU may represent an effective way of preventing the skeletal problems in patients without a restricted dietary regime.

Enzyme Replacement Therapy Ameliorates Multiple Symptoms of Murine Homocystinuria

“…33 However, the livers of the I278T mice showed only slight to moderate focal steatosis. 16 Our results are in contrast to those reports showing markedly decreased triglycerides and fatty acids in the livers of untreated mice ( Figure 3B), further supported by an overall decreased fat content in these mice 34 . Decreased fat content in I278T mice was observed earlier 17 and has been associated with a reduced expression of stearoyl-CoA desaturase-1 (SCD-1), a key enzyme involved in lipogenesis.…”

“…36 The PEG-CBS treatment completely reversed low bone mass in adult I278T mice characterized by reduced bone mineral density (BMD) and bone mineral content (BMC) compared to controls. 34 Similar impact was observed after the I278T mice were fed with a methionine-restricted diet. 18 On the contrary, betaine supplementation did not rescue bone mineralization of these mice 37 suggesting that betaine as an Hcy-lowering agent often used by HCU patients may not be as effective as ERT or methionine restriction for rescuing osteoporosis.…”

Hypermethioninemia Leads to Fatal Bleeding and Increased Mortality in a Transgenic I278T Mouse Model of Homocystinuria

“…While livers of I278T mice have roughly 2% [ 11 ], HO mice liver extracts exhibited 5% of the enzyme activity of that found in WT controls [ 19 ]. This seemingly negligible difference in residual CBS activity resulted in 40% lower plasma total Hcy concentration (243 versus 407 µM), lack of liver steatosis or fibrosis, and normal bone mineralization and fat content in HO compared to I278T mice [ 19 , 23 ]. Expression of the human CBS I278T transgene is induced by the divalent metal ions, such as zinc, received from diet or water, while the HO mice constitutively express human CBS WT transgene.…”

Behavior, body composition, and vascular phenotype of homocystinuric mice on methionine‐restricted diet or enzyme replacement therapy

“…Except for the diet-induced hyperhomocysteinemia in a mouse model (29), the HO model is so far the only genetic mouse model of HCU that recapitulates this major clinical symptom of HCU. Significantly lower plasma Hcy concentrations, markedly elevated plasma Cth levels, normal survival, unaffected bone mineralization, and body composition and lack of hepatopathy in HO mice compared with other mouse models of HCU could be responsible for prothrombotic phenotype (11,28). It has been hypothesized that hepatopathy observed in I278T (15) or KO mice (10,27,30) may cause defects in liver-dependent production of coagulation factors, whose deficit in turn would mask prothrombotic effects of elevated Hcy (27).…”