Mechanical Forces Exacerbate Periodontal Defects in Bsp-null Mice

Abstract

Bone sialoprotein (BSP) is an acidic phosphoprotein with collagen-binding, cell attachment, and hydroxyapatite-nucleating properties. BSP expression in mineralized tissues is upregulated at onset of mineralization. Bsp-null (Bsp(-/-)) mice exhibit reductions in bone mineral density, bone turnover, osteoclast activation, and impaired bone healing. Furthermore, Bsp(-/-) mice have marked periodontal tissue breakdown, with a lack of acellular cementum leading to periodontal ligament detachment, extensive alveolar bone and tooth root resorption, and incisor malocclusion. We hypothesized that altered mechanical stress from mastication contributes to periodontal destruction observed in Bsp(-/-) mice. This hypothesis was tested by comparing Bsp(-/-) and wild-type mice fed with standard hard pellet diet or soft powder diet. Dentoalveolar tissues were analyzed using histology and micro-computed tomography. By 8 wk of age, Bsp(-/-) mice exhibited molar and incisor malocclusion regardless of diet. Bsp(-/-) mice with hard pellet diet exhibited high incidence (30%) of severe incisor malocclusion, 10% lower body weight, 3% reduced femur length, and 30% elevated serum alkaline phosphatase activity compared to wild type. Soft powder diet reduced severe incisor malocclusion incidence to 3% in Bsp(-/-) mice, supporting the hypothesis that occlusal loading contributed to the malocclusion phenotype. Furthermore, Bsp(-/-) mice in the soft powder diet group featured normal body weight, long bone length, and serum alkaline phosphatase activity, suggesting that tooth dysfunction and malnutrition contribute to growth and skeletal defects reported in Bsp(-/-) mice. Bsp(-/-) incisors also erupt at a slower rate, which likely leads to the observed thickened dentin and enhanced mineralization of dentin and enamel toward the apical end. We propose that the decrease in eruption rate is due to a lack of acellular cementum and associated defective periodontal attachment. These data demonstrate the importance of BSP in maintaining proper periodontal function and alveolar bone remodeling and point to dental dysfunction as causative factor of skeletal defects observed in Bsp(-/-) mice.

Overlapping functions of bone sialoprotein and pyrophosphate regulators in directing cementogenesis

“…Bsp −/− mice feature acellular cementum deficiency, though not a complete absence, resulting in periodontal ligament (PDL) detachment and periodontal destruction, as we have reported previously [34, 39, 40] (Figure 1-D). To identify the effects on the periodontal structures associated with changes in P i /PP i regulators and other factors, we first analyzed gene expression in tooth-associated periodontal tissues by quantitative PCR (QPCR) array.…”

“…Bone sialoprotein (BSP) is a major component of the extracellular matrix (ECM) of cementum and has been shown to be essential for acellular cementum growth and function in mice [34, 39, 40]. Here we demonstrate that genetic ablation of Bsp in mice causes perturbations in plasma levels of the mineralization inhibitor, inorganic pyrophosphate (PP i ), and alters mRNA expression of PP i regulators, Alpl , Spp1 , and Ank , within periodontal tissues.…”

“…Bsp −/− mice feature deficient and defective acellular cementum, resulting in PDL detachment and periodontal breakdown [34, 39, 40]. The demonstrated function of BSP polyE domains to promote hydroxyapatite crystal nucleation and growth [50, 53–57], coupled with the previously established sensitivity of cementum to mineralization disturbances [2, 5–7, 10–16, 24–30], suggested as one hypothesis that BSP may be directly involved in initiation and/or growth of hydroxyapatite mineral in the cementum ECM.…”

“…Bsp mRNA is expressed constitutively by cementoblasts during root formation and BSP protein has been localized throughout the thickness of the acellular and cellular cementum layers [6, 34–38]. While BSP has been used as a marker of cementoblasts and cementum, its importance was not appreciated until detailed studies of dentoalveolar development in Bsp −/− mice revealed significantly reduced and nonfunctional acellular cementum, resulting in dysfunctional PDL attachment and periodontal breakdown [34, 39, 40]. While the dependence of proper cementum formation on BSP is apparent, the underlying mechanisms remain elusive.…”

Role of PHOSPHO1 in Periodontal Development and Function

“…, and Dmp1 -/-mice) feature detachment and disorganization of the PDL, widespread osteoclastic destruction of alveolar bone, and a breakdown of periodontal function akin to periodontal disease in humans, in the range of 1 to 2 months of age (Ye et al 2008;Foster et al 2013;Gasque et al 2015;Soenjaya et al 2015;Zweifler et al 2015). Although Phospho1 -/-mice exhibit defective alveolar bone mineralization, no significant periodontal destruction is evident, further confirming that acellular cementum is functional, as is the periodontal complex.…”