Kazuma Kitaguchi

Progranulin plays crucial roles in preserving bone mass by inhibiting TNF-α-induced osteoclastogenesis and promoting osteoblastic differentiation in mice.

A close correlation between atherosclerosis, inflammation, and osteoporosis has been recognized, although the precise mechanism remains unclear. The growth factor progranulin (PGRN) is expressed in various cells such as macrophages, leukocytes, and chondrocytes. PGRN plays critical roles in a variety of diseases, such as atherosclerosis and arthritis by inhibiting Tumor Necrosis Factor-α (TNF-α) signaling. The purpose of this study was to investigate the effect of PGRN on bone metabolism. Forty-eight-week old female homozygous PGRN knockout mice (PGRN-KO) (n = 8) demonstrated severe low bone mass in the distal femur compared to age- and sex-matched wild type C57BL/6J mice (WT) (n = 8) [BV/TV (%): 5.8 vs. 16.6; p < 0.001, trabecular number (1/mm): 1.6 vs. 3.8; p < 0.001]. In vitro, PGRN inhibited TNF-α-induced osteoclastogenesis from spleen cells of PGRN-KO mice. Moreover, PGRN significantly promoted ALP activity, osteoblast-related mRNA (ALP, osteocalcin) expression in a dose-dependent manner and up-regulated osteoblastic differentiation by down-regulating phosphorylation of ERK1/2 in mouse calvarial cells. In conclusion, PGRN may be a promising treatment target for both atherosclerosis and inflammation-related osteoporosis.

Effects of single or combination therapy of teriparatide and anti-RANKL monoclonal antibody on bone defect regeneration in mice

OBJECTIVE The purpose of this study is to investigate the effects of a single or combination therapy of teriparatide (TPTD) and anti-RANKL Ab (anti-murine receptor activator of nuclear factor κB ligand monoclonal antibody) on the regeneration of both cancellous and cortical bone. METHODS Nine-week-old mice underwent bone defect surgery on the left femoral metaphysis (cancellous-bone healing model) and right femoral mid-diaphysis (cortical-bone healing model). After surgery, the mice were assigned to 1 of 4 groups to receive 1) saline (5 times a week; CNT group), 2) TPTD (40μg/kg 5 times a week; TPTD group), 3) anti-RANKL Ab (5mg/kg once; Ab group), or 4) a combination of TPTD and anti-RANKL Ab (COMB group). The following analyses were performed: Time-course microstructural analysis of healing in both cancellous and cortical bone in the bone defect, the volumetric bone mineral density of the tibia with micro-computed tomography, histological, histomorphometrical, and biomechanical analysis of regenerated bone. RESULTS Regeneration of cancellous bone volume in the COMB group was the highest among the 4 groups, and this combined administration prompted medullary callus formation in the early phase of bone regeneration. On the other hand, regeneration of cortical bone volume in the COMB group was significantly higher than in the Ab group and was almost same as in the TPTD group. Histological analysis showed remaining woven bones, cartilage matrix, and immature lamellar bone in the COMB and Ab groups. However, biomechanical analysis showed that hardness and Youngs modulus of regenerated cortical bone in the COMB group was not lower than in both the CNT and TPTD groups. Volumetric bone mineral density in the tibia was significantly increased in the COMB group compared with the other 3 groups. CONCLUSION In the early phase of bone regeneration, the combination of TPTD and anti-RANKL Ab accelerates regeneration of cancellous bone in bone defects and increases cancellous bone mass in the tibia more effectively than either agent does individually, but these additive effects are not observed in the regeneration of cortical bone.

Modeling and remodeling effects of intermittent administration of teriparatide (parathyroid hormone 1-34) on bone morphogenetic protein-induced bone in a rat spinal fusion model

Background Bone morphogenetic protein (BMP)-based tissue engineering has focused on inducing new bone efficiently. However, modeling and remodeling of BMP-induced bone have rarely been discussed. Teriparatide (parathyroid hormone [PTH] 1-34) administration initially increases markers of bone formation, followed by an increase in bone resorption markers. This unique activity would be expected to accelerate the modeling and remodeling of new BMP-induced bone. Methods Male Sprague-Dawley rats underwent posterolateral spinal fusion surgery and implantation of collagen sponge containing either 50 μg recombinant human (rh)BMP-2 or saline. PTH 1-34 (60 μg/kg, 3 times/week) or saline injections were continued from preoperative week 2 week to postoperative week 12. The volume and quality of newly formed bone were monitored by in vivo micro-computed tomography and analyses of bone histomorphometry and serum bone metabolism markers were conducted at postoperative week 12. Results Microstructural indices of the newly formed bone were significantly improved by PTH 1-34 administration, which significantly decreased the tissue volumes of the fusion mass at postoperative week 12 compared to that at postoperative week 2. Bone histomorphometry and serum analyses showed that PTH administration significantly increased both bone formation and resorption markers. Analysis of the histomorphometry of cortical bone identified predominant periosteal bone resorption and endosteal bone formation. Conclusions Long-term intermittent administration of PTH 1-34 significantly accelerated the modeling and remodeling of new BMP-induced bone. Clinical relevance Our results suggest that the combined administration of rhBMP-2 and PTH 1-34 facilitates qualitative and quantitative improvements in bone regeneration, by accelerating bone modeling and remodeling.

Comparison of the effects of forefoot joint-preserving arthroplasty and resection-replacement arthroplasty on walking plantar pressure distribution and patient-based outcomes in patients with rheumatoid arthritis

Purpose The purpose of this retrospective study is to clarify the difference in plantar pressure distribution during walking and related patient-based outcomes between forefoot joint-preserving arthroplasty and resection-replacement arthroplasty in patients with rheumatoid arthritis (RA). Methods Four groups of patients were recruited. Group1 included 22 feet of 11 healthy controls (age 48.6 years), Group2 included 36 feet of 28 RA patients with deformed non-operated feet (age 64.8 years, Disease activity score assessing 28 joints with CRP [DAS28-CRP] 2.3), Group3 included 27 feet of 20 RA patients with metatarsal head resection-replacement arthroplasty (age 60.7 years, post-operative duration 5.6 years, DAS28-CRP 2.4), and Group4 included 34 feet of 29 RA patients with metatarsophalangeal (MTP) joint-preserving arthroplasty (age 64.6 years, post-operative duration 3.2 years, DAS28-CRP 2.3). Patients were cross-sectionally examined by F-SCAN II to evaluate walking plantar pressure, and the self-administered foot evaluation questionnaire (SAFE-Q). Twenty joint-preserving arthroplasty feet were longitudinally examined at both pre- and post-operation. Results In the 1st MTP joint, Group4 showed higher pressure distribution (13.7%) than Group2 (8.0%) and Group3 (6.7%) (P<0.001). In the 2nd-3rd MTP joint, Group4 showed lower pressure distribution (9.0%) than Group2 (14.5%) (P<0.001) and Group3 (11.5%) (P<0.05). On longitudinal analysis, Group4 showed increased 1st MTP joint pressure (8.5% vs. 14.7%; P<0.001) and decreased 2nd-3rd MTP joint pressure (15.2% vs. 10.7%; P<0.01) distribution. In the SAFE-Q subscale scores, Group4 showed higher scores than Group3 in pain and pain-related scores (84.1 vs. 71.7; P<0.01) and in shoe-related scores (62.5 vs. 43.1; P<0.01). Conclusions Joint-preserving arthroplasty resulted in higher 1st MTP joint and lower 2nd-3rd MTP joint pressures than resection-replacement arthroplasty, which were associated with better patient-based outcomes.