Mice lacking progesterone receptor signaling in the osteoprogenitor cells were more susceptible to collagen-induced arthritis, especially male mice. The PR
ΔPrx1-CIA mice, especially the males, had a significantly higher incidence of arthritis, joint inflammation, bone erosion, and cartilage damage compared to the normal male PR
ΔPrx1 mice or WT-CIA mice. Our findings indicate that under “normal” conditions, the presence of PR in osteoprogenitor cells might be protective against inflammatory arthritis and may also contribute to the sex differences that are observed in RA patients [
53‐
55].
A number of susceptibility genes for RA have been previously identified. The human leukocyte antigen (HLA) is a genetic site controlling immune responses in RA [
56,
57]. Several genes outside the HLA region, including
Stat4, the TRAF1-C5 locus, and PTPN22, have been reported to be associated with activation and progression of inflammation in RA [
58‐
62]. Sex disparities in genetic susceptibility to RA are understudied, and only a polymorphism in the
Cyb5a gene, which is related to androgen synthesis, has been found to be associated with risk for RA in women but not in men [
63]. Recent studies have also suggested a role for epigenetic modifications in the activation and aggressiveness of synovial fibroblasts [
64‐
67] and the X-encoded genes,
Timp1 and
IL-9R in RA [
68]. Some of these epigenetic modifications correlate with X-linked miRNA, and the presence of the second X chromosome in females may affect miRNA expression levels, potentially helping to explain sex-related autoimmunity [
69,
70]. Most of these studies on sex-specific factors affecting RA have focused on the potential effects of sex hormones due to the observation that RA improves during pregnancy and that male RA patients generally have a less severe course of illness and better response to therapy [
5,
9,
10]. Estrogen has been reported to have both pro-inflammatory and anti-inflammatory effects on the immune system while both progesterone and androgen are anti-inflammatory [
11‐
19]. The effects of hormones are mainly regulated through their hormonal receptors. The presence and proportion of estrogen and androgen receptors in different tissues and cells, including fibroblasts, chondrocytes, and bone cells, might define their roles in the sexually dimorphic pathogenesis of RA [
20‐
27]. We and others have found PR expressed in growth plate chondrocytes, osteoclasts, and osteoblasts, and PR has a critical role in peak bone mass determination in mice [
37,
71,
72]. Loss of PR signaling in osteoprogenitor cells regulates key signaling pathways for immune response, especially in males [
34]. We identified PR-targeted genes that regulated sex differences, including an “X-inactive specific transcript,”
Xist,
Mtus2,
Aldhla7/1,
Tusc5,
Cd300c, and
Pde3a [
34]. The upregulation of Xist is associated with chronic inflammation and pain in females with complex regional pain syndrome [
73] and contributes to RA progression [
74]. Cd300c and Pde3a are over-presented in RA patients [
75,
76] and are associated with inhibition of T cell immunity [
77] or response to TNF inhibitors in RA patients [
78]. Our prior and current findings [
34,
37,
39,
71] suggest that PR may regulate susceptibility to inflammatory arthritis in mice.
The presence of marginal bone erosions, detected by imaging, predicts a more severe disease course with more disability and increased morbidity. The significance of erosions in RA has been the focus of the development and approval of several agents for modifying the course of RA and has been validated in clinical trials as being able to reduce structural joint damage, including bone erosion and cartilage degradation [
79,
80]. The bone erosions in RA show a predilection for specific anatomic sites such as the radial aspects of finger joints, while the ulnar aspects are relatively spared [
81]. These focal erosions typically emerge at the site at which the synovium comes into direct contact with the bone which is known as bare areas. Anatomical factors that predispose these skeletal sites for erosion include the presence of mineralized cartilage, the insertion of ligaments at the bone surface, and inflamed tendon sheaths that enable the spread of inflammation from the tendon to the articular synovium. Articular erosion at these “bare areas” represents localized bone loss from osteolysis, which resulted from an imbalance in which bone resorption by osteoclasts is predominant over bone formation by osteoblasts. Once established, these bone erosions rarely repair despite the use of potent biologic therapeutic strategies including biologics such as TNF, IL-1, or IL-6 receptor blockade [
82‐
85]. Aberrant repair of erosions appeared as sclerosis with new bone apposition at the base of the erosion and might involve the juxta-articular bone marrow. Adipose tissue might populate the erosive area. Bone erosion seemed to correlate with on-going inflammation. Our study provides additional information to better understand the potential PR regulation of the inflammation-induced bone resorption coupling mechanism in the process of joint and bone damage and how potentiation of this coupling from lack of PR signaling contributes to bone and joint tissue loss in RA in a sex-dependent manner.
RA is a systemic autoimmune disease that induces inflammation of the synovial tissue and causes activation of inflammatory cytokines that destroy both cartilage and peri-articular bone. One of the main shortcomings for the study was the lack of measurements of cytokines and chemokines systemically or locally in the joint tissue. Therefore, we could not directly determine if the PR regulation of joint inflammation and bone loss were directly associated with changes in the cytokine/chemokine levels during the pathogenesis of IA or with the lack of PR expression in the osteoprogenitor cells. Nevertheless, our data suggested that PR might alter the susceptibility to inflammation, cartilage damage, and bone destruction in RA.