Methods: WT and Dusp-1-/- mice were fed a vitamin D deficient diet(Harlan TD.08363) for seven days and delivered a single 10ng/g bw 1,25(OH)2D3 injection via tail vein. Hematologic indices were measured at times 0, 24 and 48 hours.
Results: Upon DXA analysis, untreated Dusp-1-/- female mice have a significantly decreased skeletal and skull Bone Mineral Content (BMC) and Bone Mineral Density (BMD) at four and twelve weeks. Plasma calcium assays showed Dusp-1-/- mice on a Vitamin D deficient diet have hypercalcemia (+3.927mg/dL, P<0.05), with unsuppressed iPTH, and 21.22%(P<0.05) lower plasma alkaline phosphatase and 31.92%(P<0.05) lower TRAcP activity when compared to WT mice on the same diet. At 24 and 48 hrs 1,25(OH)2D3 treatment, alkaline phosphatase, TRAcP and iPTH levels in Dusp-1-/- mice decreased appropriately to WT levels, while plasma Ca2+ remained similarly elevated. Dusp-1-/- mice also displayed elevated renal CYP27b1 mRNA baseline expression (P<0.05), that returned to WT levels following 48 hr 1,25(OH)2D3 treatment.
Conclusion: When exposed to a vitamin D deficient diet, vitamin D resistance should produce compensatory increases in iPTH and renal CYP27b1 expression, and which should correct with exogenous 1,25(OH)2D3 administration, all of which we observe. Surprisingly, vitamin D deficient Dusp-1-/- mice exhibit PTH-dependent hypercalcemia, as evidenced by the lack of PTH suppression at supraphysiologic serum calcium concentrations at baseline. This suggests that MKP-1 is either required for differential tissue sensitivity to 1,25(OH)2D3, e.g. bone and parathyroid versus gut, or that it is needed to attenuate additional defects such as in calcium sensing or PTH secretion by the parathyroid glands.