HSP47: Disease Relevance

Hsp47 in Collagen-related Diseases

Hsp47 is an ER-resident procollagen-specific molecular chaperone which represents an essential factor in the synthesis of collagen. The expression of Hsp47 is highly tissue- and cell-specific, found predominantly in all collagen-producing cells, and constitutive expression levels coincide with collagen levels in the corresponding cell. Consequently, Hsp47 is crucially involved in the pathogenesis of collagen-related diseases such as fibrosis, keloid, and osteogenesis imperfecta (OI). Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disorder which is characterized by skeletal fragility and deformity and variable extra-skeletal manifestations, leading to short stature and truncated life cycle 203, 204. OI is a heritable bone fragility disorder that is usually caused by mutations affecting collagen type I-encoding genes 203, 205, culminating in an insufficient assembly of collagen. Other mutations, affecting collagen-modifying enzymes and chaperones have also been reported to contribute to OI 89, 206, 207. An autosomal-recessive missense mutation in the SERPINH1 gene leading to a Leu78Pro substitution in human Hsp47 has been identified to cause a severe phenotype of OI 89. Similarly, a missense mutation of Leu326Pro in Dachshunds Hsp47 has also been found as being associated with a severe OI phenotype in dogs 207. Mutant human Hsp47 is rapidly degraded by the process of ER-associated protein degradation (ERAD) leading to accumulation of protease-sensitive type I procollagen in the Golgi and its subsequent secretion 89. In contrast, the Leu326Pro mutation in Dachshunds did not lead to Hsp47 degradation but caused a partial loss of Hsp47’s functional activity, as seen in slower migration of type I collagen chains 207. A homozygous c.338_357delins22 variant in exon 2 of the human SERPINH1 gene, causing a frameshift with the formation of a premature stop codon, was recently identified by Marshall and colleagues 208. The associated OI phenotype is characterized by multiple fractures of ribs, minimal calvarial mineralisation, platyspondyly, striking compression, deformed long bones, and hydranencephaly. It is interesting to note that a functional single nucleotide polymorphism (SNP) in the promoter of the human SERPINH1 gene is associated in African American women with an increased risk for preterm premature rupture of membranes 209.

An up-regulated expression of Hsp47 is observed in a variety of fibrotic diseases including lung fibrosis and those affecting other organs 13, 150-155. These disorders are characterized by arteficial deposition of collagens in the ECM, which disassembles the typical structure and integrity and weakens the physiological functions of any organ 210. Previous studies clearly demonstrated an up-regulation of human Hsp47 in fibrotic lesions of idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (NSIP), and diffuse alveolar damage (DAD) 152, 211, 212. Also, levels of Hsp47 and collagen have been reported to expand markedly with the onset of liver fibrosis 213, intestinal fibrosis 214, and glomerulonephritis 215. Hepatic stellate cells (HSCs) were recently identified as the key cell type in liver fibrogenesis as they differentiate into collagen-producing myofibroblasts upon exposure to inflammatory conditions 216. Hsp47 is also associated with fibrosis following myocardial infarction 217 and has been localized in artherosclerotic arteries 218. In scleroderma patients, the up-regulated expressions of Hsp47 and collagen have been attributed to the enhanced production of profibrogenic TGF-β 12. Moreover, the elevated Hsp47 expression could also be detected in the circulation of the patients, suggesting Hsp47 could be used as a potential pathological marker to assess the progression of scleroderma, and also to describe the systemic fibrosis of this disorder 12.


Hsp47 in Rheumatic Autoimmune Diseases

Hsp47 protein and autoantibody levels are significantly elevated in the sera of patients with rheumatic autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus, Sjögren’s syndrome, and mixed connective tissue disease (MCTD) 219. In particular, the sera of MCTD patients contained considerably enhanced levels of Hsp47 antigen and anti-Hsp47 autoantibodies compared to healthy controls. From these findings it can be hypothesized that the simultaneous manifestation of systemic inflammation and Hsp47 over-expression may cause leakage of Hsp47 from fibrotic lesions into the periphery, where released Hsp47 induces the formation of anti-Hsp47 autoantibodies. The high Hsp47 protein and autoantibody levels in MCTD patients might therefore be considered as being a useful marker of MCTD 219. In a more recent study, synovial fibroblasts (SFs) from RA patients have been reported to express significantly up-regulated levels of Hsp47 in comparison to normal subjects rendering Hsp47 as being a reliable marker for quantifying SFs in human synovial tissue 220.


Hsp47 in Alzheimer’s Disease

Hsp47 has been implicated in Alzheimer’s disease (AD), the most common neurodegenerative disorder, with a prevalence of approximately 2% in developed countries. AD is pathologically characterized by the formation of senile plaques of amyloid-β protein (Aβ) and tangles of hyperphosphorylated Tau protein, leading to a progressive loss of neurons and synapses as well as cerebral amyloid angiopathy 221-223. Work by the group of Ferdinando Di Cunto revealed an association of the β-amyloid precursor protein (APP) with Hsp47 which was found as being enriched in amyloid plaques in mouse models of AD and some AD patients 224. In the same study, pharmacological inhibition or knockdown of Hsp47 was able to reduce the levels of secreted Aβ peptides implying Hsp47 as being a potential target for preventing the formation and/or growth of amyloid plaques in AD patients.


Hsp47 in Cancer and Type 2 Diabetes mellitus

Fibrotic diseases and cancer share several characteristics; both pathologies are characterized by genetic alterations, uncontrolled cell proliferation, altered cell interactions and communication and tissue invasion. Accordingly, cancer cells often show up-regulated levels of Hsp47 as can be found in pancreatic ductal adenocarcinoma, breast cancer, cervical squamous cell carcinoma, glioblastoma, head and neck squamous cell carcinoma, scirrhous gastric carcinoma, and ulcerative colitis-associated carcinomas (reviewed by Ibrahim et al., 2018) 164. The correlation between Hsp47 and cancer might be due to the fact that Hsp47 is a product of the SERPINH1 gene located to chromosome 11q13, a region usually amplified in human cancers 165, 166. Various ECM proteins including collagen have also been demonstrated as being expressed in association with Hsp47 to provide necessary biophysical and biochemical signals to drive growth, migration and invasion of cancer cells 167. TGF-β signaling obviously seems to play a crucial role in the regulation of the Hsp47 expression, since the TGF-β signaling pathway conquers Hsp47-induced carcinogenesis and stemness of glioblastoma 168. Most recently, over-expression of Hsp47 has been identified as an independent precision predictor for unfavourable prognosis in clear cell renal cell carcinoma 225, esophageal squamous cell carcinoma (ESCC) 226, and colorectal cancer 227. This is in contrast to findings obtained for laryngeal squamous cell carcinoma (LSCC), where cancerous laryngeal tissues showed a markedly decreased expression of Hsp47 compared to non-cancerous tissues and this down-regulation correlated with poor prognosis in LSCC patients 228. A down-regulation of Hsp47 was also noted in biopsies from wounds of patients with type 2 diabetes mellitus (T2DM) correlating with wound healing impairment in these subjects 229.