Decline in calcitonin receptor expression in osteocytes with age

Abstract

We have previously shown that co-administration of the transient osteoclast inhibitor, salmon calcitonin (sCT), blunts the anabolic effect of parathyroid hormone (PTH) in young rats and increases osteocytic expression of the bone formation inhibitor sclerostin (Sost). To determine whether this also occurs in adult animals, we co-administered sCT with PTH to 6-month-old sham-operated (SHAM) and ovariectomised (OVX) rats. While sCT reduced the stimulatory effect of PTH on serum amino-terminal propeptide of type 1 procollagen levels, in contrast to its influence in young rats, sCT did not reduce the anabolic effect of PTH on femoral bone mineral density, tibial trabecular bone volume or bone formation rate in 6-month-old SHAM or OVX rats. Quantitative real-time PCR analysis of femoral metaphyses collected 1 and 4 h after a single PTH injection confirmed a significant increase in mRNA levels for interleukin 6 (Il6) and ephrinB2 (EfnB2), and a significant reduction in Sost and dentin matrix protein-1 (Dmp1) in response to PTH. However, in contrast to observations in young rats, these effects were not modified by co-administration of sCT, nor did sCT significantly modify Sost, Dmp1, or matrix extracellular phosphoglycoprotein (Mepe) mRNA levels. Furthermore, while CT receptor (CTR) mRNA (Calcr) was readily detected in GFPC osteocytes isolated from young (3-week-old) DMP1-GFP mice, Calcr levels in osteocytes declined as mice aged, reaching levels that were undetectable in long bone at 49 weeks of age. These data indicate that osteocyte-mediated responses to CT are most likely to be of physiological relevance in young rodents.

Abaloparatide Is an Anabolic, but Does It Spare Resorption?

“…This has been assessed using both biochemical markers and histomorphometry and implies that the induced formation is taking place predominantly on quiescent surfaces. (49)(50)(51)(52)(53)(54)(55)(56)(57) The same outcome is reported by Varela and colleagues, (48) where aged osteopenic rats were treated with three doses of abaloparatide (1, 5, and 25 mg/kg), resulting in substantial doseresponsive increases in BMD and bone formation, assessed by histomorphometry, without any significant increase in resorption parameters. It is interesting that such low doses of abaloparatide were used in this study, given the choice in the clinical trial of a dose 4 times higher than that of teriparatide, and the known very much higher dose of PTHrP(1-36) required in mice and in human subjects.…”

“…(49)(50)(51)(52)(53)(54)(55)(56)(57) The same outcome is reported by Varela and colleagues, (48) where aged osteopenic rats were treated with three doses of abaloparatide (1, 5, and 25 mg/kg), resulting in substantial doseresponsive increases in BMD and bone formation, assessed by histomorphometry, without any significant increase in resorption parameters. It is interesting that such low doses of abaloparatide were used in this study, given the choice in the clinical trial of a dose 4 times higher than that of teriparatide, and the known very much higher dose of PTHrP(1-36) required in mice and in human subjects.These doses of abaloparatide are in the same range of dosedependent effects observed in studies of PTH(1-34) in aged osteopenic rats, where similar dose-responsive anabolic effects with PTH(1-34) were achieved at 0.1, 0.3, 3, and 30 mg/kg (49) and with 5 and 15 mg/kg.(50) In these latter two studies and many other studies in aged ovariectomized (OVX) rats, some using low PTH doses, others using relatively high doses (100 mg/kg), (51)(52)(53)(54)(55)(56)(57) the anabolic effect was achieved without any increase in osteoclast surface or resorption markers. …”

“…(50) In these latter two studies and many other studies in aged ovariectomized (OVX) rats, some using low PTH doses, others using relatively high doses (100 mg/kg), (51)(52)(53)(54)(55)(56)(57) the anabolic effect was achieved without any increase in osteoclast surface or resorption markers.…”

Calcitonin suppresses intervertebral disk degeneration and preserves lumbar vertebral bone mineral density and bone strength in ovariectomized rats

“…Collagen II-positive staining in the annulus fibrosis was much weaker in the OVX+V group than that in the sham and OVX+CT and groups. MMP-1-and MMP-13-positive staining in the annulus fibrosis was stronger in the OVX+V group than in the sham and OVX+CT groups reduced as rodents age, the CT-receptor (CTR) was identified in bone-matrix-embedded osteocytes [25,26]. Moreover, articular cartilage chondrocytes from osteoarthritis (OA) patients do indeed express CTR, which makes articular cartilage a pharmacological target for salmon CT [27].…”

Osteoclast formation elicited by interleukin-33 stimulation is dependent upon the type of osteoclast progenitor

“…Some osteoclasts can have low activity, including those derived from RAW264.7 cells, which leads to inconclusive results. CTR is highly specific in the myelomonocytic lineage for osteoclasts, although osteocytes as well as some cell types not found in bone can express CTR (Gooi et al, 2014;Nicholson et al, 1986). This has led us previously to investigate the use of anti-CTR antibodies to identify murine osteoclasts in culture (peptides derived from human CTR seem to be poorly immunogenic in rabbits); we therefore have employed this approach with IL-33 + TGFβ-treated RAW264.7 cells.…”