TRPV1 deletion impaired fracture healing and inhibited osteoclast and osteoblast differentiation

Abstract

Fracture healing, in which osteoclasts and osteoblasts play important roles, has drawn much clinical attention. Osteoclast deficiency or decreased osteoblast activity will impair fracture healing. TRPV1 is a member of the Ca2+ permeable cation channel subfamily, and pharmacological inhibition of TRPV1 prevents ovariectomy-induced bone loss, which makes TRPV1 a potential target for osteoporosis. However, whether long term TRPV1 inhibition or TRPV1 deletion will affect the fracture healing process is unclear. In this study, we found that the wild-type mice showed a well-remodeled fracture callus, whereas TRPV1 knockout mice still had an obvious fracture gap with unresorbed soft-callus 4 weeks post-fracture. The number of osteoclasts was reduced in the TRPV1 knockout fracture callus, and osteoclast formation and resorption activity were also impaired in vitro. TRPV1 deletion decreased the calcium oscillation frequency and peak cytoplasmic concentration in osteoclast precursors, subsequently reducing the expression and nuclear translocation of NFATc1 and downregulating DC-stamp, cathepsin K, and ATP6V. In addition, TRPV1 deletion caused reduced mRNA and protein expression of Runx2 and ALP in bone marrow stromal cells (BMSCs) and reduced calcium deposition in vitro. Our results suggest that TRPV1 deletion impairs fracture healing, and inhibited osteoclastogenesis and osteogenesis.

Psoralen accelerates bone fracture healing by activating both osteoclasts and osteoblasts

“…Based on these data, we suggest that simultaneously activating osteoclasts for bone absorption and osteoblasts for bone formation leads to accelerated bone fracture healing. Conversely, and in support of our findings, inhibition of osteoclast and osteoblast differentiation by transient receptor potential cation channel subfamily V member 1 deletion has been reported to impair fracture healing in rats (12).…”

“…After the newly formed bone connects the fractured bone ends, bone resorption induced by osteoclasts and bone formation conducted by osteoblasts continues in what is called the bone remodeling process. Enhancing osteoclastogenesis would accelerate cartilage resorption and promote the replacement of cartilaginous callus by hard callus (11, 12). Increasing osteoblastogenesis during fracture healing would also promote bone union.…”

Cellular biology of fracture healing

“…Pharmacological disruption of osteoclastogenesis by inhibiting transient receptor potential cation channel subfamily V member 1 (TRPV1) has been used as a treatment strategy for post‐menopausal bone loss. However, fracture studies using TRPV1 knockout mice demonstrated an essential role of osteoclasts in soft‐callus formation and remodeling . The decreased osteoclast number in TRPV1 mice lead to enlarged malformed calluses and persistent fracture gaps.…”

Nerves in Bone: Evolving Concepts in Pain and Anabolism

“…High systemic doses of capsaicin have also been used to induce cell death selectively in small sensory, primarily unmyelinated, neurons in bone and other tissues . Though originally thought to be specific to nerve, recent reports have suggested that TRPV1 is also expressed in cells of the chondrocyte, osteoblast, and osteoclast lineages . Last, protein gene product 9.5 (PGP9.5) is a ubiquitin‐protein hydrolase that is often used as a pan‐neuronal marker for purposes of quantification of nerves in and on the bone …”