Influences of obese (ob/ob) and diabetes (db/db) genotype mutations on lumber vertebral radiological and morphometric indices: skeletal deformation associated with dysregulated systemic glucometabolism

Abstract

Background: Both diabetes and obesity syndromes are recognized to promote lumbar vertebral instability, premature osteodegeneration, exacerbate progressive osteoporosis and increase the propensity towards vertebral degeneration, instability and deformation in humans.

Methods: The influences of single-gene missense mutations, expressing either diabetes (db/db) or obese (ob/ob) metabolic syndromes on vertebral maturation and development in C57BL/KsJ mice were evaluated by radiological and macro-morphometric analysis of the resulting variances in osteodevelopment indices relative to control parameters between 8 and 16 weeks of age (syndrome onset @ 4 weeks), and the influences of low-dose 17-B-estradiol therapy on vertebral growth expression evaluated.

Results: Associated with the indicative genotypic obesity and hyper-glycemic/-insulinemic states, both db/db and ob/ob mutants demonstrated a significant (P < or = 0.05) elongation of total lumbar vertebrae column (VC) regional length, and individual lumbar vertebrae (LV1-5) lengths, relative to control VC and LV parameters. In contrast, LV1-5 width indices were suppressed in db/db and ob/ob mutants relative to control LV growth rates. Between 8 and 16 weeks of age, the suppressed LV1-5 width indices were sustained in both genotype mutant groups relative to control osteomaturation rates. The severity of LV1-5 width osteosuppression correlated with the severe systemic hyperglycemic and hypertriglyceridemic conditions sustained in ob/ob and db/db mutants. Low-dose 17-B-estradiol therapy (E2-HRx: 1.0 ug/ 0.1 ml oil s.c/3.5 days), initiated at 4 weeks of age (i.e., initial onset phase of db/db and ob/ob expressions) re-established control LV 1-5 width indices without influencing VC or LV lengths in db/db groups.

Conclusion: These data demonstrate that the abnormal systemic endometabolic states associated with the expression of db/db and ob/ob genomutation syndromes suppress LV 1-5 width osteomaturation rates, but enhanced development related VC and LV length expression, relative to control indices in a progressive manner similar to recognized human metabolic syndrome conditions. Therapeutic E2 modulation of the hyperglycemic component of diabetes-obesity syndrome protected the regional LV from the mutation-induced osteopenic width-growth suppression. These data suggest that these genotype mutation models may prove valuable for the evaluation of therapeutic methodologies suitable for the treatment of human diabetes- or obesity-influenced, LV degeneration-linked human conditions, which demonstrate amelioration from conventional replacement therapies following diagnosis of systemic syndrome-induced LV osteomaturation-associated deformations.

Figure 1

Radiological comparisons between the lumbar vertebral segments (LV 1–5) for control, obese (ob/ob) and diabetes (db/db) genotype-mutants groups are represented (x12.5) as indicators of length and width index parameters measured relative to the severity of diabetes-obesity syndrome aberrations for body weight and systemic endocrine/metabolic (Table 2) indices.

Figure 2

Representation of average lumber vertebral column (VC) lengths, as well as individual lumber vertebrae (LV) length and width indices, are denoted for control (+/?), obese (ob/ob) and diabetes (db/db) mutant genotypes as groups means (± SEM) at 8 and 16 weeks of age. Significant (P ≤ 0.05) intergroup differences (i.e., control v.s. genotype mutant type) at each designed age are denoted by asterisks (*). Age-dependent (i.e., 8 v.s. 16 week values for the same genotype) intragroup differences are denoted by #.

Figure 3

Influences on control (+/?) and diabetes (db/db)-mutant C57BL/KsJ group average lumbar vertebrae (LV) length and width indices following oil- or E2-HRx regimes at 8 and 16 weeks of age. All values are denoted as groups means (± SEM), with significant (P ≤ 0.05) intergroup (i.e. control v.s. diabetes genotypes for indicated HRx regimes) differences are denoted by asterisks (*)