Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation

Abstract

PTH (1-34) is the only FDA-approved anabolic agent for osteoporosis treatment in the U.S., but its mechanisms are not completely understood. This study investigated PTH effects on osteogenic cells at various stages of differentiation and proliferation using an engineered bone growth model in vivo. Ossicles were generated from bone marrow stromal cells (BMSCs) implanted in immunocompromised mice. Three weeks of PTH (40μg/kg/d) or vehicle treatment initiated 1 day, 1, 2, or 3wks after BMSC implantation resulted in an anabolic response in PTH-treated implants (via histomorphometry and microCT) in all treatment groups. A novel in vivo tracking strategy with luciferase tagged BMSCs and weekly bioluminescent imaging of ossicles revealed increased donor cell proliferation in PTH-treated ossicles. The greatest increase occurred during the first week, and the activity remained elevated in PTH-treated implants over time. Zoledronic acid (ZA) was combined with PTH to delineate interactive mechanisms of these bone active agents. Combining ZA with PTH treatment reduced the PTH-mediated increase in luciferase BMSC activity, serum osteocalcin, and serum tartrate resistant acid phosphotase-5b (TRAP-5b) but ZA did not reduce the PTH-induced increase in total bone. Since zoledronic acid reduced PTH-induced proliferation without reducing bone volume, these data suggests that combining PTH and bisphosphonate therapy warrants further investigation in the treatment of bone disorders.

Parathyroid hormone regulates the distribution and osteoclastogenic potential of hematopoietic progenitors in the bone marrow

“…It also may inhibit apoptosis in mature osteoblasts, which might prolong the anabolic effects of PTH. (12)(13)(14)(15)(16)(17)(18)(19)30) However, to fully appreciate the responses of bone to PTH, it is also necessary to understand how PTH administration affects other type of cells in the bone microenvironment that are implicated in bone turnover. Osteoclasts are another potential target of PTH action because the physiologic activities of osteoblasts and osteoclasts are tightly coupled.…”

“…Continuous administration of PTH induces catabolic effects on bone, whereas intermittent PTH administration exerts anabolic effects. (12)(13)(14)(15)(16)(17)(18)(19) Currently, once-daily injection of human PTH is approved by the Food and Drug Administration as treatment for osteoporosis in the United States. In addition, it could have potential for the treatment of other conditions that require new bone formation.…”

Tissue engineered bone using select growth factors: A comprehensive review of animal studies and clinical translation studies in man

“…Combination of BMP-7 with BMP-2 constitutes an additive approach where two osteogenic factors are hypothesised to further enhance the osteogenic outcome, whilst keeping individual dosages low (Koh et al, 2008;Wang et al, 2012). Alternatively, combinations with VEGF or TGF-β3 (Ripamonti et al, 2010) constitute mutualistic approaches where the angiogenic factor induces vessel ingrowth into the defect (2 fold (Zhang et al, 2010a)), the chondrogenic factor induces cartilaginous matrix production to fill the defect void, and the osteogenic factor induces resultant callus mineralisation and eventual bone formation (three lineages important for recapitulation of the in vivo bone healing cascade).…”

“…Wang et al (2012) delivered 5 μg of BMP-2 and 5 μg of BMP-7 via an implanted collagen sponge within a minipig calvarial defect, and demonstrated a 1.5 fold increase in bone formation compared to either growth factor alone. Koh et al (2008) also investigated BMP-2 and BMP-7 indirect delivery via implantation of transduced cells within a mouse calvarial defect. The study showed a maximum 2-fold increase in bone formation compared to individual growth factor administration.…”

Intermittent parathyroid hormone (1–34) application regulates cAMP-response element binding protein activity to promote the proliferation and osteogenic differentiation of bone mesenchymal stromal cells, via the cAMP/PKA signaling pathway

“…Parathyroid hormone [PTH ] is currently the only anabolic agent approved by the Food and Drug Administration (FDA) for the treatment of osteoporosis in the USA (1). It is established that intermittent PTH (1-34) administration increases mass, strength and mineral density of bone, and improves bone microarchitecture and fracture healing (2)(3)(4).…”