Treating osteoporosis by targeting parathyroid hormone to bone

Ponnapakkam, Tulasi; Katikaneni, Ranjitha; Sakon, J.; Stratford, Robert E.; Gensure, Robert C.

doi:10.1016/j.drudis.2013.07.015

Cited by 59 publications

(33 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The CBD from clostridial collagenases has a unique property, as it binds to collagen, adopting a triple‐helix structure, but does not bind to denatured collagen (gelatin) (Matsushita et al ., ). A fusion protein consisting of a growth factor and a bacterial CBD as an anchoring unit can potentially be delivered as a targeted therapeutic drug (Katikaneni et al ., , ; Ponnapakkam et al ., , ; Saito et al ., ; Ueno et al ., ). We previously established a method for accelerating periosteal bone formation using collagen materials decorated with collagen‐binding bFGF protein fused with a PKD domain and a CBD, which are derived from C. histolyticum class II collagenase (ColH) (Uchida et al ., ).…”

Section: Discussionmentioning

confidence: 98%

Enhancement of periosteal bone formation by basic fibroblast-derived growth factor containing polycystic kidney disease and collagen-binding domains fromClostridium histolyticumcollagenase

Uchida

Matsushita

Nishi

et al. 2015

J Tissue Eng Regen Med

View full text Add to dashboard Cite

Recombinant basic fibroblast growth factor (bFGF) is a potent mitogen for mesenchymal cells that accelerates bone union and repair when applied locally at defect sites. However, because bFGF diffuses rapidly from bone defect sites, repeated dosing is required for sustained therapeutic effect. We previously fused the collagen-binding domain (CBD) and polycystic kidney disease (PKD) domain of Clostridium histolyticum class II collagenase (ColH) to bFGF and demonstrated that the fusion protein markedly enhances bone formation when loaded onto collagen materials used for grafting. However, systemic injection of a fusion protein consisting of parathyroid hormone (PTH) and a CBD was shown to accelerate bone formation in an osteoporosis model more rapidly than treatment with a PTH-PKD-CBD fusion protein. Here, we compared the biological properties of two collagen-binding forms of bFGF, bFGF-CBD and bFGF-PKD-CBD. Both fusion proteins promoted the in vitro proliferation of periosteal mesenchymal cells, indicating that they had biological activity similar to that of native bFGF. In vivo periosteal bone formation assays in rat femurs showed that both bFGF-CBD and bFGF-PKD-CBD induced periosteal bone formation at higher rates than collagen sheet alone and bFGF. However, bFGF-PKD-CBD markedly enhanced bone formation and had higher collagen-binding ability than bFGF-CBD in in vitro protein release assays. Taken together, these results suggest that the PKD domain increases the retention of bFGF at graft sites by enhancing collagen-binding affinity. Therefore, bFGF-PKD-CBD-collagen composite appears to be a promising material for bone repair in the clinical setting. Copyright © 2015 John Wiley & Sons, Ltd.

show abstract

Section: Discussionmentioning

confidence: 98%

Enhancement of periosteal bone formation by basic fibroblast-derived growth factor containing polycystic kidney disease and collagen-binding domains fromClostridium histolyticumcollagenase

Uchida

Matsushita

Nishi

et al. 2015

J Tissue Eng Regen Med

View full text Add to dashboard Cite

show abstract

“…The benefits of PTH treatment include an increase in bone mass through a combination of new bone modeling and the sustained bone remodeling with a positive balance as well as improved bone material properties (13,18,29,32,59). However, the potency of PTH precipitously declines and there is an FDAmandated two-year limit on treatment (18), emphasizing the need for new strategies that improve the efficacy of the drug, such as by combining hormone treatment with an anti-catabolic drug or targeting PTH directly to bone (26,83). Neutralizing intrinsic pathways that temper PTHinduced osteoblast secretion of bone matrix might improve drug efficacy.…”

Section: Introductionmentioning

confidence: 99%

Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality

Shao

Wichern

Childress

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

A goal of osteoporosis therapy is to restore lost bone with structurally sound tissue. Mice lacking the transcription factor nuclear matrix protein 4 ( Nmp4, Zfp384, Ciz, ZNF384) respond to several classes of osteoporosis drugs with enhanced bone formation compared with wild-type (WT) animals. Nmp4−/− mesenchymal stem/progenitor cells (MSPCs) exhibit an accelerated and enhanced mineralization during osteoblast differentiation. To address the mechanisms underlying this hyperanabolic phenotype, we carried out RNA-sequencing and molecular and cellular analyses of WT and Nmp4−/− MSPCs during osteogenesis to define pathways and mechanisms associated with elevated matrix production. We determined that Nmp4 has a broad impact on the transcriptome during osteogenic differentiation, contributing to the expression of over 5,000 genes. Phenotypic anchoring of transcriptional data was performed for the hypothesis-testing arm through analysis of cell metabolism, protein synthesis and secretion, and bone material properties. Mechanistic studies confirmed that Nmp4−/− MSPCs exhibited an enhanced capacity for glycolytic conversion: a key step in bone anabolism. Nmp4−/− cells showed elevated collagen translation and secretion. The expression of matrix genes that contribute to bone material-level mechanical properties was elevated in Nmp4−/− cells, an observation that was supported by biomechanical testing of bone samples from Nmp4−/− and WT mice. We conclude that loss of Nmp4 increases the magnitude of glycolysis upon the metabolic switch, which fuels the conversion of the osteoblast into a super-secretor of matrix resulting in more bone with improvements in intrinsic quality.

show abstract

“…More recently, derivatives of anthraquinone were found to bind hydroxyapatite mineral and may be used to deliver nonsteroidal anti-inflammatory drugs to arthritic bone [59]. It is also possible to target the organic phase of bone by using collagen binding domain (CBD) peptides derived from Clostridium histolyticum ( ColH ) collagenase, where CBD can be a synthetic extension of a peptide drug [60 •• ]. …”

Section: Controlled Drug Delivery To Bonementioning

confidence: 99%

Local and targeted drug delivery for bone regeneration

Newman

Benoit

2016

Current Opinion in Biotechnology

View full text Add to dashboard Cite

While experimental bone regeneration approaches commonly employ cells, technological hurdles prevent translation of these therapies. Alternatively, emulating the spatiotemporal cascade of endogenous factors through controlled drug delivery may provide superior bone regenerative approaches. Surgically placed drug depots have clinical indications. Additionally, noninvasive systemic delivery can be used as needed for poorly healing bone injuries. However, a major hurdle for systemic delivery is poor bone biodistribution of drugs. Thus, peptides, aptamers, and phosphate-rich compounds with specificity toward proteins, cells, and molecules within the regenerative bone microenvironment may enable the design of targeted carriers with bone biodistribution greater than that achieved by drug alone. These carriers, combined with osteoregenerative drugs and/or stimuli-sensitive linkers, may enhance bone regeneration while minimizing off-target tissue effects.

show abstract

Treating osteoporosis by targeting parathyroid hormone to bone

Cited by 59 publications

References 29 publications

Enhancement of periosteal bone formation by basic fibroblast-derived growth factor containing polycystic kidney disease and collagen-binding domains fromClostridium histolyticumcollagenase

Enhancement of periosteal bone formation by basic fibroblast-derived growth factor containing polycystic kidney disease and collagen-binding domains fromClostridium histolyticumcollagenase

Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality

Local and targeted drug delivery for bone regeneration

Contact Info

Product

Resources

About