Bone Abstracts

Objective: Osteocalcin, an osteoblast-derived hormone, is among the most abundant proteins in bone and is involved in the regulation of whole-body metabolism, muscle adaptation, and reproduction. High bone turnover and low bone mass are clinical hallmarks of Osteogenesis Imperfecta (OI), a bone disease mainly caused by mutations in the collagen-I gene. Recently, we have shown that growing mice with a severe dominant form of OI, Col1a1Jrt/+ mice, displayed significantly elevated serum levels of undercarboxylated osteocalcin (uOCN) along with an altered glucose/insulin metabolism and energy expenditure. Further, these mice are protected against high-fat diet induced obesity but not insulin resistance. To further confirm the role of uOCN, we crossed Col1a1Jrt/+ mice (OI) with mice lacking one or both osteocalcin genes (OCN+/−, OCN−/−) to generate OI/OCN mice.

Methods: At 4 and 8 weeks of age, wild-type (WT/WT) and OI/OCN mice were phenotypically characterized and random glucose (RG) measurements along with glucose tolerance (GT) test were performed.

Results: To generate OI/OCN mice, fertile OCN+/− and OI mice were used. Within the first generation, about 27% of generated mice were WT/OCN+/−, 24% OI/WT, 26% OI/OCN+/−, 22% WT/WT, and 1% were found dead. For further breeding, OI/OCN+/− mice were used and gave birth to pups with a genetic distribution of about 18% OI/OCN+/− or WT/OCN+/−, 21% OI/OCN−/−, 12% WT/OCN−/−, 6% OI/WT, and 12% were found dead. Compared to WT/WT, 4-week old mice harboring the genotype OI/WT, OI/OCN+/−, and OI/OCN−/− were smaller in size and up to 20% lower in body mass which declined to about 15% difference at 8-weeks of age. At 4-weeks of age, OI/OCN+/− and OI/OCN−/− mice exhibited lower RG levels than WT/WT littermates (P<0.05). However, only OI/OCN+/− mice revealed improved GT (P<0.01) while OI/OCN−/− mice did not differ from WT/WT. At 8-weeks of age, no significant differences in RG or GT were found in OI/OCN+/− or OI/OCN−/− mice compared to WT/WT.

Conclusion: Here we show for the first time that knock-out of both osteocalcin genes restored glucose tolerance to WT levels in mice with severe dominant OI, strongly supporting the causative role of osteocalcin driving alteration in glucose/insulin metabolism in OI mice.

Disclosure: The authors declared no competing interests.