Alveolar bone loss: mechanisms, potential therapeutic targets, and interventions

Abstract

This article reviews recent research into mechanisms underlying bone resorption and highlights avenues of investigation that may generate new therapies to combat alveolar bone loss in periodontitis. Several proteins, signaling pathways, stem cells, and dietary supplements are discussed as they relate to periodontal bone loss and regeneration. RGS12 is a crucial protein that mediates osteoclastogenesis and bone destruction, and a potential therapeutic target. RGS12 likely regulates osteoclast differentiation through regulating calcium influx to control the calcium oscillation-NFATc1 pathway. A working model for RGS10 and RGS12 in the regulation of Ca(2+) oscillations during osteoclast differentiation is proposed. Initiation of inflammation depends on host cell-microbe interactions, including the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Oral p38 inhibitors reduced lipopolysaccharide (LPS)-induced bone destruction in a rat periodontitis model but showed unsatisfactory safety profiles. The p38 substrate MK2 is a more specific therapeutic target with potentially superior tolerability. Furthermore, MKP-1 shows anti-inflammatory activity, reducing inflammatory cytokine biosynthesis and bone resorption. Multipotent skeletal stem cell (SSC) populations exist within the bone marrow and periosteum of long bones. These bone-marrow-derived SSCs and periosteum-derived SSCs have shown therapeutic potential in several applications, including bone and periodontal regeneration. The existence of craniofacial bone-specific SSCs is suggested based on existing studies. The effects of calcium, vitamin D, and soy isoflavone supplementation on alveolar and skeletal bone loss in post-menopausal women were investigated. Supplementation resulted in stabilization of forearm bone mass density and a reduced rate of alveolar bone loss over 1 yr, compared with placebo. Periodontal attachment levels were also well-maintained and alveolar bone loss suppressed during 24 wk of supplementation.

Keywords: menopause; mesenchymal stem cells; p38 MAPK; p38 inhibitors; regulator of G protein signaling; skeletal stem cells.

Figure 1.

Interaction of RGS10 and RGS12 with the target components (Yang et al., 2007). RAW264.7 cells were induced with RANKL for 96 hr. (A) N-type calcium channel binds with RGS12, but not RGS10. (B) Lane 1: positive control. RGS10 and RGS12 expressed in RANKL-induced osteoclasts. Lane 2: I P, CaM; IB, RGS12 and RGS10. (c) Lane 1: positive controls. RANKL-induced osteoclasts. Lanes 2 and 3: I P, CaR; IB, RGS10, 12, and CaR. RGS, regulator of G protein signaling; RANKL, Receptor activator of nuclear factor kappa-B ligand; CaM, calmodulin; CaR, calcium-sensing receptor.

Figure 2.

A proposed working model of RGS proteins in the regulation of the Ca²⁺ oscillation-NFATc1 signal pathway for osteoclast (OC) differentiation. We propose that RGS10 and RGS12 play different functions in the regulation of Ca²⁺ oscillations and OC differentiation. RGS10 competitively binds with Ca²⁺/CaM and phosphatidylinositol (3,4,5)-triphosphate (PIP3) in a Ca²⁺-dependent manner to internally regulate calcium release from the ER; conversely, RGS12 might interact with Ca²⁺ channels and CaR at the cell membrane to regulate calcium influx during OC differentiation (Yang and Li, 2007a). Thus, RGS10 and RGS12 respectively regulate periodic Ca²⁺ influx and the ER internal release of Ca²⁺ and contribute to the generation and maintenance of Ca²⁺ oscillations and OC differentiation. RGS, regulator of G protein signaling; OC, osteoclast; CaM, calmodulin; PIP3, phosphatidylinositol (3,4,5)-triphosphate; ER, endoplasmic reticulum; CaR, calcium-sensing receptor.

Figure 3.

A. actinomycetemcomitans LPS induces significant linear bone loss, which is blocked by p38 inhibitor, SD282. (A) Reformatted μCT isoform display from eight-week A. actinomycetemcomitans LPS-injected rat maxillae exhibits dramatic palatal and interproximal bone loss. Landmarks used for linear measurements were the cemento-enamel junction (CEJ) to the alveolar bone crest (ABC). Differences between these anatomic locations in defined locations of 2-D displays determined alveolar bone loss. (B) Linear bone loss as measured from the CEJ to ABC (mean ± SEM). Significant bone loss (p < .01) was observed between control (n = 6) and A. actinomycetemcomitans LPS-injected rats (n = 12). Significant reduction of LPS-induced periodontal bone loss (**p < .01 for SD-282 [15 mg/kg; n = 8] and *p < .05 for SD-282 [45 mg/kg; n = 8]) (Kirkwood et al., 2007). Reproduced with permission.

Figure 4.

MKP-1 gene transfer alleviated bone resorption in rats after LPS challenge. Eight-week-old male Sprague-Dawley rats (17 rats/ group) were injected with either Ad. MKP-1, or Ad. LacZ control (1 × 10⁹ pfu in 4 μL), or with HEPES-buffered saline (4 μL). Forty-eight hr after the adenovirus injection, the rats were injected with 2 μL of either 20 μg of LPS (from A. actinomycetemcomitans) or phosphate buffered saline (PBS) 3 times a wk for 4 wk. (a) Representative microcomputed tomography images of rat maxillae from indicated treatment groups. (b) Volumetric analysis of bone loss levels (n = 7 for PBS groups, n = 10 for LPS groups, *p < .05) (Yu et al., 2011). Ad, recombinant adenovirus. Reproduced with permission.

Figure 5.

Percentage change in forearm bone mineral density (BMD) over 1 yr in post-menopausal women receiving daily supplementation with vitamin D, calcium, and isoflavone aglycone or placebo. Single dose = 500 mg calcium, 10 mg soy isoflavone; double dose = 1,000 mg calcium, 20 mg isoflavone. Both supplementation groups also received 110 international units (IU) of vitamin D (Grossi et al., 2004).