Hepatocyte growth factor and alternative splice variants - expression, regulation and implications in osteogenesis and bone health and repair

ABSTRACT

Introduction: Bone marrow-derived mesenchymal stem cells (MSCs) can differentiate into multiple cell types, including osteoblasts, chondrocytes, and adipocytes. These pluripotent cells secrete hepatocyte growth factor (HGF), which regulates cell growth, survival, motility, migration, mitogenesis and is important for tissue development/regeneration. HGF has four splice variants, NK1, NK2, NK3, and NK4 which have varying functions and affinities for the HGF receptor, cMET. HGF promotes osteoblastic differentiation of MSCs into bone forming cells, playing a role in bone development, health and repair.

Areas Covered: This review will focus on the effects of HGF in osteogenesis, bone repair and bone health, including structural and functional insights into the role of HGF in the body.

Expert Opinion: Approximately 6.2 million Americans experience a fracture annually, with 5-10% being mal- or non-union fractures. HGF is important in priming MSCs for osteogenic differentiation in vitro and is currently being studied to assess its role during bone repair in vivo. Due to the high turnover rate of systemic HGF, non-classic modes of HGF-treatment, including naked-plasmid HGF delivery and the use of HGF splice variants (NK1 & NK2) are being studied to find safe and efficacious treatments for bone disorders, such as mal- or non-union fractures.

KEYWORDS:

• Hepatocyte Growth Factor
• HGF
• Bone
• Osteoblastic Differentiation
• Osteoblasts
• Osteoclasts
• cMET

Article highlights

• Accumulating evidence supports the concept that HGF promotes bone maturation and is involved in maintenance and osteoblastic differentiation of bone-derived mesenchymal stem cells.

• HGF consists of full-length HGF (also known as SF), along with alternative splice variants; endogenously expressed NK1 and NK2, together with NK3 and NK4.

• The reported increased stability and low turnover rate of NK1 suggest that NK1 could provide novel therapeutic modalities in combination with stem cells for treatment of bone diseases.

• Local expression of HGF in the microenvironment of a bone fracture showed enhanced healing of the bone fracture in animal models.

• To maintain a therapeutic level of HGF, a new approach has been developed using a naked-plasmid-based delivery of HGF, systemically increasing HGF levels, which appears to be a safe, effective in vivo method—currently being used in phase II clinical trials for critical limb ischemia.

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Declaration of interest

The authors were supported by National Institute of Health/National Institute of Arthritis and Musculoskeletal Diseases (GRANT # 5F32AR062990-04), Miami VA Medical Center, University of Miami School of Medicine. KM Curtis is a postdoctoral fellow funded in part by NIH/NIAMS F32 Postdoctoral Grant #5F32AR062990-04. GA Howard is funded in part through veterans affairs career scientist award and veterans affairs merit review grant. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.